Novel Heterocyclic Derivatives Useful as SHP2 Inhibitors

ABSTRACT

The present invention provides a compound of formula I, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, the present invention provides a pharmaceutical composition comprising the said compound.

TECHNICAL FIELD

This invention relates to certain novel heterocyclic derivatives (Formula I) as SHP2 inhibitors which is shown as formula I, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, this invention is directed to fused heterocyclic derivatives useful as inhibitors of SHP2, methods for producing such compounds and methods for treating a SHP2-mediated disorder.

BACKGROUND ART

SHP2 (The Src Homolgy-2 phosphatease) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that harbors a classical tyrosine phosphatase domain and two N-terminal Src homology 2 (SH2) domains and a C-terminal tail. The two SH₂ domains control the subcellular localization and functional regulation of SHP2. In its inactive state, the N-terminal SH₂ domain blocks the PTP domain and this autoinhibition is relieved by binding of the SH₂ domains to specific phosphotyrosine sites on receptors or receptor-associated adaptor proteins. The stimulation, for example, by cytokines or growth factors leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.

SHP2 is widely expressed and participated in multiple cell signaling processes, such as the Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR, and insulin receptors and NF-kB pathways, in which plays an important role in proliferation, differentiation, cell cycle maintenance and migration.

The hyperactivation of SHP2 catalytic activity caused by either germline or somatic mutations in PTPN11 have been identified in patients with Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, myelodysplastic syndrome, B cell acute lymphoblastic leukemia/lymphoma, and acute myeloid leukemia. In addition, activating mutation s of PTPN11 have been found in solid tumors as well, such as lung cancer, colon cancer, melanoma, neuroblastoma, and hepatocellular carcinoma. Therefore, the presence of activated or up-regulated SHP2 protein in human cancers and other disease make SHP2 an excellent target for development of novel therapies. The compounds of the present invention fulfill the need of small molecules in order to inhibit the activity of SHP2.

SUMMARY OF INVENTION

The present invention relates to certain novel heterocyclic compounds useful as SHP2 inhibitors and their use for treating a SHP2 mediated disorder. The compounds of the invention have the general structure as Formula I or a pharmaceutically acceptable salt:

ring A is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—;

each of R_(G) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted;

ring B is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

T is absent, O, NR₁ or CR₁R₂;

each of R₁ and R₂ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or

R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅;

p is 0, 1, 2, 3 or 4;

each of R₃ and R₄ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or

R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR₅, and each of the ring systems is independently optionally substituted or unsubstituted;

each of R₅ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy;

q is 0, 1, 2, 3 or 4;

W is absent, O, S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, —C₁₋₆alkylene-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

when ring C is absent, Y₅ is CR_(5a)R_(5b), NR_(5a) or O, and Y₆ is CR_(6a)R_(6b), NR_(6a) or O;

when ring C is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring;

-   -   i) Y₅ is CR_(5a) or N, and Y₆ is CR_(6a) or N, when the “         ” in the term “Y₅         Y₆” represents a single bond; or     -   ii) Y₅ is C, and Y₆ is C, when the “         ” in the term “Y₅         Y₆” represents a double bond;

each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

each of R_(a) is independently selected from hydrogen, deuterium, halogen, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₆alkoxy, —C₁₋₆alkyl, —C₃₋₈cycloalkyl,-C₁₋₆alkylene—NR_(a1)R_(a2), —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₆alkylene—CO—OR_(a1), —C₁₋₆alkylene-(3-10 membered heterocyclic), —C₁₋₆alkylene-(5-10 membered heteroaryl), —C₁₋₆alkylene—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(a1)—CO—C₁₋₆alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), _(lo)carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C₁₋₆alkyl, —COO—C₁₋₆alkyl, —CO—C₁₋₆alkylene—NR_(a1)R_(a2), —CO—NR_(al)-(3-10 membered heterocyclic), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO—(3-10 membered heterocyclic), —O—C₁₋₆alkylene—CO—OR_(a1), —O—C₁₋₆alkylene-C —NR_(a1)R_(a2), —O—C₁₋₆alkylene—NR_(a1)R_(a2), —O—C₃₋₁₀carbocyclic, —O—(3-10 membered heterocyclic), —NR_(a1)—CO—C₁₋₆alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(al)—CO—(5-10 membered heteroaryl), —NR_(a1)—CO—C₃₋₈cycloalkyl,—NR_(a1)—C₁₋₆alkylene—NR_(a1)R_(a2), —NR_(al) —C₁₋₆alkylene-(3-10 membered heterocyclic), —NR_(al) —C₁₋₆alkylene-(5-10 membered heteroaryl), —NR_(ar) S 0₂C₁₋₆alkyl, —S—C₁₋₆alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₆alkyl, —SO₂—C₁₋₆alkyl, —PO(C₁₋₆alkyl)₂, —PO(C₁₋₆alkoxy)₂, −3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or

two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; or

R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted;

each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula I, ring A is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring A is a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring A is a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring A is

represents a single bond or a double bond;

X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1);

each of R_(X1) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl,

X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO;

each of R_(X2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF_(S), —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO—(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X1)and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3);

each of R_(X3) is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene—C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene—C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X2) and R_(X3)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ;

X₄ is N, S, NR_(X4), C(R_(x4))₂ or CR_(X4);

each of R_(X4) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or a 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X3) and R_(X4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5);

each of R_(X5) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X4) and R_(X5) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂;

each of R_(X6) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy, or

R_(X5) and R_(X6)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(Xl)is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₂ is N, S, NR_(X2), C(R_(X2))₂,CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₄alkyl, —C₁₋₃alkoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHC 0-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, X₂ is N, S, NR_(X2), CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF_(S), —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R_(X1)and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X1)and R_(X2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X1)and R_(X2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene—C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene—C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl,—O—C₁₋₆alkylene-C₁₋₆alkyl, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₃alkyl, —C₁₋₃alkoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene—C_(h3)alkyl, —O—C₅₋₆aryl or —O—C₁₋₃alkylene-C₅₋₆aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene—C₁₋₃alkyl, —O—C₅₋₆aryl or —O—C₁₋₃alkylene-C₅₋₆aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene—C₁₋₃alkyl, —O—C₅₋₆aryl or —O—C₁₋₃alkylene—C₅₋₆aryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R_(X2) and R_(X3) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X2) and R_(X3) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X2) and R_(X3) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, an 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R_(X3) and R_(X4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X3) and R_(X4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X3) and R_(X4) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R_(X4) and R_(X5)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X4) and R_(X5)together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X4) and R_(X5)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R_(X5) and R_(X6) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X5) and R_(X6) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered. heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(X5) and R_(X6) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring A is selected from

In some embodiments of Formula I, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring B is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2,3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3, 4, 5 or 6heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, wherein ring B is a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2,3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring B is a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, a 7 membered carbocyclic ring, a 8 membered carbocyclic ring, a 9 membered carbocyclic ring, a 10 membered carbocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, a 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring B is

Y₁ is N or CR_(Y1),

R_(Y1) is selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C_(s-lo)aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

Y₂ is N or CR_(Y2);

R_(Y2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(Y1)and R_(Y2)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

when the “

” in the term “^(Y3)

Y₄” represents a single bond, Y₃ is NR_(Y3) or C(R_(Y3))₂, and Y₄ is

CO, C(R_(Y4))₂ or NR_(Y4);

when the “

” in the term “^(Y3)

Y₄” represents a double bond, Y₃ is N or CR_(Y3), and Y₄ is N or

CR_(Y4);

R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH , —C₁₋₆alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with —OH, or —C₁₋₆alkoxy; or

R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R_(Y1)and R_(Y2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, wherein R_(Y1)and R_(Y2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(Y1)and R_(Y2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —CO—C₃₋₈heterocyclic ring, —C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with —OH, or —C₁₋₆alkoxy.

In some embodiments of Formula I, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —C₁₋₆alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl, —C₁₋₃alkyl substituted with —OH or —C₁₋₃alkoxy.

In some embodiments of Formula I, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, ethyl substituted with —OH, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R_(Y3) and R_(Y4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(Y3) and R_(Y4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring B is selected from

In some embodiments of Formula I, each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula I, each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula I, each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula I, each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅.

In some embodiments of Formula I, R₁ and R₂ together with the carbon atom to which they are both attached form CO.

In some embodiments of Formula I, R₁ and R₂ together with the carbon atom to which they are both attached form C═NR₅.

In some embodiments of Formula I, each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula I, each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula I, each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula I, each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R₃ and R₄ together with the carbon atom to which they are both attached form 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R₃ and R₄ together with the carbon atom to which they are both attached form 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, R₃ and R₄ together with the carbon atom to which they are both attached form 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, 9 membered heterocyclic ring, 10 membered heterocyclic ring, 5 membered heteroaromatic ring, 6 membered heteroaromatic ring, 7 membered heteroaromatic ring, 8 membered heteroaromatic ring, 9 membered heteroaromatic ring, 10 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, each of R₅ is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, each of R₅ is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, each of R₅ is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, —C₁₋₆alkylene-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula I, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₃alkyl, —CO—OC₁₋₃alkyl, —C₁₋₃alkylene-O—C₁₋₃alkoxy, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula I, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkylene-O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula I, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkylene-O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula I, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkylene-O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula I, ring C is selected from

In some embodiments of Formula I, each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula I, each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula I, each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula I, each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula I, each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula I, each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula I, each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each of R_(a) is independently hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₃alkoxy, —C₁₋₄alkyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene—NRA_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene —CO—OR_(a)′, —C₁₋₃alkylene -(3-8 membered heterocyclic), —C₁₋₃alkylene -(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—C —NR_(a1)R_(a2), —C₁₋₃alkylene —NR_(a1)—C —C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −5-8 membered heteroaryl, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—(3-8 membered heterocyclic), —O—C₁₋₃alkylene—CO—OR_(a1), —O—C₁₋₃alkylene-C —NR_(a1)R_(a2), —O—C₁₋₃alkylene —NR_(al) R_(a2), —O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(al)—CO—C₃₋₆cycloalkyl, —NR_(a1)—C₁₋₃alkylene —NR_(a1)R_(a2), —NR_(al)—C₁₋₃alkylene -(3-8 membered heterocyclic), —NR_(al)—C₁₋₃alkylene -(5-8 membered heteroaryl), —NR_(al)—SO₂C₁₋₃alkyl, -S —C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments of Formula I, each of R_(a) is independently hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, butyl, isobutyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene—CO—OR_(a1), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −5-8 membered heteroaryl, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR_(ar)(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —O—C-(3-8 membered heterocyclic), —O—C₁₋₃alkylene—CO—OR_(a1), —O—C₁₋₃alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene—NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(al) —C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(al)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂C₁₋₃alkyl, —S—C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments of Formula I, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula I, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, R_(a) and R_(w) with the atom to which they are both attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 5 membered heteroaryl ring, a 6 membered heteroaryl ring, a 5 membered heterocyclic ring or a 6 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula I, each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula I, each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula I, each of R_(a1) and R_(w) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula I, each of R_(a1) and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

The present invention further provides the compound of Formula II or a pharmaceutically acceptable salt thereof:

X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1);

each of R_(X1) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl,

X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO;

each of R_(X2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF_(S), —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X1)and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3);

each of R_(X3) is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene—C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X2) and R_(X3)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₄ is N, S, NR_(X4), C(R)_(X4), C(R_(X4))₂ or CR_(X4);

each of R_(X4) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl,-C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X3) and R_(X4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5);

each of R_(X5) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X4) and R_(X5)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

represents a single bond or a double bond;

G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—;

each of R_(G) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted;

Y₁ is N or CR_(Y1),

R_(Y1) is selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C_(s-lo)aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

Y₂ is N or CR_(Y2);

R_(Y2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₁₋₆aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(Y1)and R_(Y2)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

when the “

” in the term “Y₃

Y₄” represents a single bond, Y₃ is NR_(Y3) or C(R_(Y3))₂, and Y₄ is CO, C(R_(Y4))₂ or NR_(Y4);

when the “

” in the term “Y₃

Y₄” represents a double bond, Y₃ is N or CR_(Y3), and Y₄ is N or CR_(Y4);

R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH ,—C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

T is absent, O, NR₁ or CR₁R₂;

each of R₁ and R₂ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or

R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅;

p is 0, 1, 2 or 3;

each of R₃ and R₄ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or

R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR₅, and each of the ring systems is independently optionally substituted or unsubstituted;

each of R₅ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

q is 0, 1, 2, 3 or 4;

W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC_(I-6)alkyl, —C₁₋₆alkyl-O— C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

when ring C is absent, Y₅ is CR_(5a)R_(5b), NR_(5a) or O, and Y₆ is CR_(6a)R_(6b), NR_(6a) or O;

when ring C is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring;

-   -   i) Y₅ is CR_(5a) or N, and Y₆ is CR_(6a) or N, when the “         ” in the term “Y₅         Y₆” represents a single bond; or     -   ii) Y₅ is C, and Y₆ is C, when the “         ” in the term “Y₅         Y₆” represents a double bond;

each of R_(Ya) and R_(5b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

each of R_(a) is independently hydrogen, deuterium, halogen, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₆alkoxy, —C₁₋₆alkyl, —C₃₋₈cycloalkyl, —C₁₋₆alkylene—NR_(a1)R_(a2), —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₆alkylene—CO—OR_(a1), —C₁₋₆alkylene-(3-10 membered heterocyclic), —C₁₋₆alkylene-(5-10 membered heteroaryl), —C₁₋₆alkylene—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(a1)—CO—NRA_(a2), —C₁₋₆alkylene—NR_(a1)—CO—C₁₋₆alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₄₀carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C₁₋₆alkyl, —CO—C₁₋₆alkyl, —CO—C₁₋₆alkylene—NRA_(a2), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C₁₋₆alkylene—CO—OR_(a1), —O—C₁₋₆alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₆alkylene—NR_(a1)R_(a2), —O—C₃₄₀carbocyclic, —O-(3-10 membered heterocyclic), —NR_(a1)—CO—C₁₋₆alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-10 membered heteroaryl), —NR_(a1)—CO—C₃₋₈cycloalkyl,—NR_(a1)—C₁₋₆alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₆alkylene-(3-10 membered heterocyclic), —NR_(a1)—C₁₋₆alkylene-(5-10 membered heteroaryl), —NR_(a1)—SO₂C₁₋₆alkyl, —S—C₁₋₆alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₆alkyl, —SO₂—C₁₋₆alkyl, —PO(C₁₋₆alkyl)₂, —PO(C₁₋₆alkoxy)₂, −3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or

two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaomatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted;

each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl. C(R_(X1))₂,

In some embodiments of Formula II, X₁ is N, S, NR_(X1), or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy. C(R_(X1))₂,

In some embodiments of Formula II, X₁ is N, S, NR_(X1), or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy. C(R_(X1))₂,

In some embodiments of Formula II, X₁ is N, S, NR_(X1), or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy. C(R_(X1))₂,

In some embodiments of Formula II, X₁ is N, S, NR_(X1), or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy. C(R_(X1))₂,

In some embodiments of Formula II, X₁ is N, S, NR_(X1), or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxyl, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, -S F₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, -S F₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, -S F₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R_(m)and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X1)and R_(X2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X1)and R_(X2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene-C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene—C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₃alkyl, —C₁₋₃alkoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene—C₁₋₃alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene—C₁₋₃alkoxy, —O—C₅₋₈aryl or —O—C₁₋₃alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene—C₁₋₃alkoxy, —O—C₅₋₈aryl or —O—C₁₋₃alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R_(X2) and R_(X3)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X2) and R_(X3)together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X2) and R_(X3)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxyl, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxyl, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R_(X3) and R_(X4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X3) and R_(X4)together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X3) and R_(X4)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R_(X4) and R_(X5)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X4) and R_(X5)together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(X4) and R_(X5)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, ring A is selected from

In some embodiments of Formula II, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or −50₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R_(Y1)and R_(Y2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(Y1)and R_(Y2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(Y1)and R_(Y2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R_(Y3) and R_(Y4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(Y3) and R_(Y4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R_(Y3) and R_(Y4) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, ring B is selected from

In some embodiments of Formula II, each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula II, each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula II, each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula II, each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅.

In some embodiments of Formula II, R₁ and R₂ together with the carbon atom to which they are both attached form CO.

In some embodiments of Formula II, R₁ and R₂ together with the carbon atom to which they are both attached form C═NR₅.

In some embodiments of Formula II, each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula II, each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula II, each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula II, each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R₃ and R₄ together with the carbon atom to which they are both attached form a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, R₃ and R₄ together with the carbon atom to which they are both attached form a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC_(I-6)alkyl, —C₁₋₆alkyl-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula II, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₃alkyl, —CO—OC₁₋₃alkyl, —C₁₋₃alkyl-O—C_(h3)alkoxy, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula II, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl-O—C_(h3)alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula II, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl-O—C_(h3)alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula II, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl-O—C_(h3)alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, a 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula II, ring C is selected from

In some embodiments of Formula II, each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula II, each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula II, each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula II, each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula II, each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula II, each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula II, each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₃alkoxy, —C₁₋₃alkyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene—CO—OR_(a1), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −5-10 membered heteroaryl, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene—NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂C₁₋₃alkyl, —S—C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments of Formula II, each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene—CO—OR_(a1), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene—CO—OR_(a1), —O—C₁₋₃alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene—NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, -O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(al)—SO₂C₁₋₃alkyl, -S-C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments of Formula II, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula II, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula II, each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula II, each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula II, each of R_(a1) and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula II, each of R_(a1) and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, the compound is of Formula II-a:

X₁, X₂, X₃, X₄, X₅, G, R_(Y1), R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein.

In some embodiments of Formula II, the compound is of Formula II-b

X₁, X₂, X₃, X₄, X₅, G, R_(Y1), R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein.

In some embodiments of Formula II, the compound is of Formula II-c

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Y1), R_(Y2), R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein.

The present invention further provides the compound of Formula III or a pharmaceutically

acceptable salt thereof:

X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1);

each of R_(X1) is selected from hydrogen, deuterium, halogen, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO;

each of R_(X2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —SF_(S), —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X1)and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl,-C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl or —O—C₁₋₆alkylene-C₁₋₆alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X2) and R_(X3)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ;

X₄ is N, S, NR_(X4), C(R_(X4))₂or CR_(X4);

each of R_(X4) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X3) and R_(X4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

X₅ is N, NR_(X5) C(R_(X5))₂ or CR_(X5);

each of R_(X5) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or

R_(X4) and R_(X5)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

represents a single bond or a double bond;

G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or -5 0₂—NR_(G)—;

each of R_(G) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted;

Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

Y₂ is N or CR_(Y2);

R_(Y2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

when the “

” in the term “Y₃

Y₄” represents a single bond, Y₃ is NR_(Y3;) and Y₄ is CO;

when the “

” in the term “Y₃

Y₄” represents a double bond, Y₃ is N or CR_(Y3), and Y₄ is N or CR_(Y4);

R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH ,—C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

T is absent, O, NR₁ or CR₁R₂;

each of R₁ and R₂ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or

R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅;

p is 0, 1, 2 or 3;

each of R₃ and R₄ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or

R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR₅, and each of the ring systems is independently optionally substituted or unsubstituted;

each of R₅ is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxyl;

q is 0, 1, 2, 3 or 4;

W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC_(I-6)alkyl, —C₁₋₆alkyl-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

when ring C is absent, Y₅ is CR_(5a)R_(5b), NR_(5a) or O, and Y₆ is CR_(6a)R_(6b), NR_(6a) or O;

when ring C is 5-12 membered aromatic ring, 5-12 membered heteroaromatic ring or 5-12 membered heterocyclic ring;

-   -   i) Y₅ is CR_(5a) or N, and Y₆ is CR_(6a) or N, when the “         ” in the term “Y₅         Y₆” represents a single bond; or     -   ii) Y₅ is C, and Y₆ is C, when the “         ” in the term “Y₅         Y₆” represents a double bond;

each of R_(Ya) and R_(5b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl;

each of R_(a) is independently hydrogen, deuterium, halogen, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₆alkoxy, —C₃₋₈cycloalkyl, —C₁₋₆alkylene—NR_(a1)R_(a2), —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₆alkylene-C —C₁₋₆alkylene-(3-10 membered heterocyclic), —C₁₋₆alkylene-(5-10 membered heteroaryl), —C₁₋₆alkylene—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(ar)CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(ar)CO—C₁₋₆alkyl, —CO—NR_(a1)R_(a2), —COO—C₁₋₆alkyl, —CO—CO—NR_(a1)R_(a2), —C₃₄₀carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C₁₋₆alkyl, —CO—C₁₋₆alkylene—NR_(a1)R_(a2), —CO—NR_(ar)(3-10 membered heterocyclic), —CO—NR_(ar)(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C₁₋₆alkylene—CO—OR_(a1), —O—C₁₋₆alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₆alkylene—NR_(a1)R_(a2), —O—C₃₄₀carbocyclic, —O-(3-10 membered heterocyclic), —NR_(ar)CO—C₁₋₆alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(ar)C 045-10 membered heteroaryl), —NR_(ar)CO—C₃₋₈cycloalkyl,—NR_(ar)C₁₋₆alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₆alkylene-(3-10 membered heterocyclic), —NR_(a1)—C₁₋₆alkylene-(5-10 membered heteroaryl), —NR_(ar) S 0₂C₁₋₆alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO₂C₁₋₆alkyl, —PO(C₁₋₆alkyl)₂, —PO(C₁₋₆alkoxy)₂, −3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or

two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring, −3-6 membered heterocyclic ring or −3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; or

R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted;

each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted

In some embodiments of Formula III, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X, is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₄alkyl, —C₁₋₃alkoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHC 0-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, R_(X1)and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X1)and R_(X2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X1)and R_(X2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl or —O—C₁₋₆alkylene-C₁₋₆alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl or —O—C₁₋₆alkylene-C₁₋₆alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₃alkyl,-C₁₋₃alkoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene—C_(h3)alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene—C_(h3)alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene—C_(h3)alkyl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, R_(X2) and R_(X3)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X2) and R_(X3)together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X2) and R_(X3) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl,-C₁₋₃alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, R_(X3) and R_(X4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X3) and R_(X4)together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X3) and R_(X4)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, R_(X4) and R_(X5) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X4) and R_(X5) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R_(X4) and R_(X5) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, ring A is selected from

In some embodiments of Formula III, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independent selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—,

—C(R_(G))₂— or −50₂—NR_(G)—; each of R_(G) is independent selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independent selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or -C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH ,—C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH ,—C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, carboxyl, —C —C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH ,—C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH ,—C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, ring B is selected from

In some embodiments of Formula III, each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula III, each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula III, each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula III, each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅.

In some embodiments of Formula III, R₁ and R₂ together with the carbon atom to which they are both attached form CO.

In some embodiments of Formula III, R₁ and R₂ together with the carbon atom to which they are both attached form C═NR₅.

In some embodiments of Formula III, each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula III, each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula III, each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula III, each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, R₃ and R₄ together with the carbon atom to which they are both attached form 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R₃ and R₄ together with the carbon atom to which they are both attached form 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, R₃ and R₄ together with the carbon atom to which they are both attached form 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, 9 membered heterocyclic ring, 10 membered heterocyclic ring, 5 membered heteroaromatic ring, 6 membered heteroaromatic ring, 7 membered heteroaromatic ring, 8 membered heteroaromatic ring, 9 membered heteroaromatic ring, 10 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC_(I-6)alkyl, —C₁₋₆alkyl-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula III, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₃alkyl, —CO—OC₁₋₃alkyl, —C₁₋₃alkyl-O—C_(h3)alkoxy, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula III, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl-O—C_(h3)alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula III, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl-O—C_(h3)alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula III, W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl-O—C_(h3)alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, a 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

In some embodiments of Formula III, ring C is selected from

In some embodiments of Formula III, each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula III, each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula III, each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula III, each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula III, each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula III, each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula III, each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₃alkoxy, —C₁₋₄alkyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene—NRA_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene —CO-0R_(a)′, —C₁₋₃alkylene -(3-8 membered heterocyclic), —C₁₋₃alkylene -(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—C—NR_(a1)R_(a2), —C₁₋₃alkylene —NR_(a1)—C —C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −3-8 membered heterocyclic, —C—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene —C—OR_(a1), —O—C₁₋₃alkylene —C —NR_(a1)R_(a2), —O—C₁₋₃alkylene —NR_(al) R_(a2),—O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(al)—CO—C₃₋₆cycloalkyl, —NR_(a1)—C₁₋₃alkylene —NR_(a1)R_(a2), —NR_(al)—C₁₋₃alkylene -(3-8 membered heterocyclic), —NR_(al)—C₁₋₃alkylene -(5-8 membered heteroaryl), —NR_(al)—SO₂C₁₋₃alkyl, -S —C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments of Formula III, each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, butyl, isobutyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene—CO—OR_(a1), —C₁₋₃alkylene -(3-8 membered heterocyclic), —C₁₋₃alkylene -(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₃alkylene —NR_(a1)—C—C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −3-8 membered heterocyclic, —C—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —C-(3-8 membered heterocyclic), —O—C₁₋₃alkylene -C -0R_(a1), —O—C₁₋₃alkylene —C—NR_(a1)R_(a2), —O—C₁₋₃alkylene —NR_(al) R_(a2),—O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(al)—CO—C₃₋₆cycloalkyl, —NR_(a1)—C₁₋₃alkylene —NR_(a1)R_(a2), —NR_(al)—C₁₋₃alkylene -(3-8 membered heterocyclic), —NR_(al)—C₁₋₃alkylene -(5-8 membered heteroaryl), —NR_(al)—SO₂C₁₋₃alkyl, -S —C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments of Formula III, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, R_(a) and R, with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments of Formula III, R_(a) and R, with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, R_(a) and R, with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, R_(a) and R, with the atom to which they are both attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 5 membered heteroaryl ring, a 6 membered heteroaryl ring, a 5 membered heterocyclic ring or a 6 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.

In some embodiments of Formula III, each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.

In some embodiments of Formula III, each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.

In some embodiments of Formula III, each of R_(a1) and _(Rae) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.

In some embodiments of Formula III, each of R_(a1) and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula III, the compound is of Formula III-a:

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein.

In some embodiments of Formula II, the compound is of Formula III-b:

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein.

In some embodiments of Formula III, the compound is of Formula III-c:

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein.

In some embodiments of Formula III, the compound is of Formula III-d:

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein.

In some embodiments of Formula III, the compound is of Formula III-e:

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined herein. In some embodiments, the present invention provides a compound selected from the group consisting of:

1 ethyl (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5--2- carboxylate 2 (S)-1′-(5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 3 (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazine-2-carboxylic acid 4 (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazine-2-carboxamide 5 ethyl (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2-amino-3-chloropyridin- 4-yl)thio)-5-methylpyrazine-2-carboxylate 6 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2 4′-piperidin]-1-amine 7 (S)-1′-(6-amino-5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 8 (S)-1′-(4-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrimidin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 9 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 10 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-(methylamino)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 11 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-(dimethylamino)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 12 (S)-1′-(6-amino-5-(thiazol-4-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 13 (S)-1′-(6-amino-5-(thiazol-2-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 14 (S)-1′-(6-amino-5-(quinolin-3-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 15 (S)-5-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-3-carbonitrile 16 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-N-methyl-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine 17 (S)-1′-(5-((3,5-dichloropyridin-4-yl)thio)pyrazin-2-yl)-5,6,7-trifluoro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine 18 (S)-1-amino-1′-(2-((2-cyanopyridin-3-yl)thio)pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-4-carbonitrile 19 (S)-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)pyrazin-2-yl)-6-(methylthio)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 20 (S)-1-(5-((5-(4-amino-2-(tert-butyl)-4,6-dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-1′- yl)pyrazin-2-yl)thio)-2-chlorophenyl)ethan-1-one 21 (S)-1′-(5-((3-chloro-2-(isopropylamino)pyridin-4-yl)thio)pyrazin-2-yl)-6-(methylsulfonyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 22 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7,7-d2-5-amine 23 (S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazin-2-yl)methanol 24 (S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2-amino-3-chloropyridin-4- yl)thio)-5-methylpyrazin-2-yl)methanol 25 (S)-1′-(3-bromo-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 26 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazine-2-carbonitrile 27 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazine-2-carboxamide 28 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazin-2-ol 29 (S)-1′-(6-amino-3-bromo-5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 30 (S)-5-amino-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-((2,3- dichlorophenyl)thio)pyrazine-2-carbonitrile 31 (S)-5-amino-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-((2,3- dichlorophenyl)thio)pyrazine-2-carboxamide 32 (S)-1′-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 33 (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)pyridin-3-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 34 (S)-1′-(4-((2-amino-3-chloropyridin-4-yl)thio)phenyl)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 35 (S)-1′-(4-((2-amino-3-chloropyridin-4-yl)thio)isoquinolin-1-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 36 (S)-6-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-3-(2,3- dichlorophenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 37 (S)-6-(1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2,3-dichlorophenyl)- 5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 38 (S)-6-(1-amino-5,6,7-trifluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methyl-3-(5- methylthiophen-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 39 (S)-2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3- dichlorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 40 (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2-amino-3- chloropyridin-4-yl)thio)-3-methylpyrimidin-4(3H)-one 41 (S)-1′-(6-amino-5-((4-chlorothiazol-2-yl)thio)pyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 42 (S)-1-amino-1′-(5-((4-amino-5-bromopyrimidin-2-yl)thio)-1-methyl-6-oxo-1,6-dihydropyridin-2- yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 43 (S)-6-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-((3-chloro-2- methoxypyridin-4-yl)thio)-1-methyipyridin-2(1H)-one 44 (S)-1-amino-1′-(4-(6-bromonaphthalen-2-yl)thiazol-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-6-carbonitrile 45 (S)-1′-(6-amino-5-(2-chloro-3-methylphenyl)pyrazin-2-yl)-6-bromo-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 46 (S)-1′-(5-(3-amino-2-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-1,6-diamine 47 (S)-1′-(6-amino-5-(2-chloro-3-methylphenyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-1,6-diamine 48 (S)-1′-(6-(5-chlorothiophen-2-yl)pyridazin-3-yl)-5-methyl-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 49 (S)-1′-(6′-chloro-[3,3′-bipyridazin]-6-yl)-5-methyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1- amine 50 (S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 51 (R)-1′-(5-(2,3-dichloro-5-methoxyphenyl)pyridin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]- 2-amine 52 (S)-6′-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1′-methyl-2′-oxo-1′,2′- dihydro-[3,3′-bipyridine]-2-carbonitrile 53 (S)-6′-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1′-methyl-2′-oxo-1′,2′- dihydro-[3,3′-bipyridine]-2-carboxamide 54 (S)-1′-(4-(3-methoxyphenyl)cyclohexyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]- 5-amine 55 (S)-1-amino-1′-(6-((3-amino-2-chlorophenyl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-6-carbonitrile 56 1-(5-((5-((1S)-1-amino-6-(methylsulfinyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin- 2-yl)thio)-2-chlorophenyl)ethan-1-one 57 (S)-1′-(5-(pyrimidin-2-ylthio)pyrazin-2-yl)-6-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 58 (S)-6-bromo-5-fluoro-1′-(5-(quinolin-4-ylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 59 (S)-6-(4-amino-4,6-dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-1′-yl)-3-(3- (trifluoromethyl)pyridin-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 60 (S)-2-(1-amino-6-chloro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3,5- dichloropyridin-4-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 61 (S)-1′-(7-(5-chloropyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-3-amine 62 (S)-1′-(7-(3-chloropyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1H,3H-spiro[phenalene-2,4′- piperidin]-1-amine 63 (R)-1′-(3-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3,4-dihydro-1H- spiro[naphthalene-2,4′-piperidin]-3-amine 64 (S)-6-amino-2-(1-amino-7-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methyl-5- phenylpyrimidin-4(3H)-one 65 (S)-1-amino-1′-(4-amino-6-oxo-5-(pyridazin-3-ylthio)-1,6-dihydropyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-7-carbonitrile 66 (S)-1-amino-1′-(1-methyl-6-oxo-5-(pyrazin-2-yl)-1,6-dihydropyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-7-carbonitrile 67 (S)-2-(1-amino-6-chloro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((4- isopropylphenyl)thio)pyrimidin-4(3H)-one 68 (S)-4-amino-6-(1-amino-6-bromo-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2- chloro-3-methylphenyl)-1-methylpyridin-2(1H)-one 69 (S)-6-(4-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-4-amino-3-(4- (trifluoromethyl)phenyl)pyridin-2(1H)-one 70 (S)-6′-(1-amino-4-hydroxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2′-oxo-1′,2′-dihydro- [3,3′-bipyridine]-2-carbonitrile 71 (S)-1′-(3-bromo-5-(1H-indol-6-yl)-6-methylpyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 72 (S)-3-(4-amino-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-5-methyl-6-(2- oxoindolin-7-yl)pyrazine-2-carbonitrile 73 (S)-1′-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 74 (S)-1′-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thio)pyridin-3-yl)-6-chloro-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 75 (S)-1′-(4-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 76 (S)-1′-(5-((2,3-dichlorophenyl)thio)thiazol-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-7-amine 77 (R)-1′-(4-((3-chloropyridin-4-yl)thio)thiazol-2-yl)spiro[indoline-2,4′-piperidin]-3-amine 78 (R)-1′-(2-(7-chloro-1H-indol-1-yl)thiazol-4-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-amine 79 (R)-1′-(2-((2-(trifluoromethyl)phenyl)thio)thiazol-5-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3- amine 80 (S)-(5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)(2,3- dichlorophenyl)methanone 81 (S)-2-(1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(indolin-1-yl)-3-methyl- 3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 82 (S)-1′-(5-((1,2,3,4-tetrahydroquinolin-8-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[b]naphthalene-2,4′-piperidin]-1-amine 83 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-1-amine 84 1′-(5-((3-amino-2-chlorophenyl)thio)-6-methylpyrazin-2-yl)-1-methyl-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 85 (R)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)-1H-indol-4-yl)-3H-spiro[benzofuran-2,4′- piperidin]-3-amine 86 (S)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)isoquinolin-3-yl)-5,6-dibromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 87 (S)-4-((5-(5-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-aminopyrazin-2- yl)thio)-3-chloro-1-methylpyridin-2(1H)-one 88 (S)-5-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-((2,3- dichlorophenyl)thio)-6-(hydroxymethyl)pyridin-3-ol 89 (S)-6-bromo-1′-(5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 90 (S)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl)-6-bromo- 1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 91 (S)-1′-(8-((2-amino-3-chloropyridin-4-yl)thio)pyrido[4,3-d]pyrimidin-5-yl)-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 92 (S)-3-(5-(1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridin-2-yl)-4,5- dichlorophenol 93 (S)-1-amino-1′-(5-(5-methylthiophen-2-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]- 6-ol 94 (S)-1′-(5-(1H-indol-7-yl)pyrazin-2-yl)-5-ethyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 95 (S)-1′-(5-(cyclohex-1-en-1-yl)pyrazin-2-yl)-5-isopropyl-1,3-dihydrospiro[indene-2,4′-piperidin]- 1-amine 96 (S)-N-(1-amino-1′-(5-(2-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-6-yl)methanesulfonamide 97 (S)-1′-(5-((4-(trifluoromethyl)pyrimidin-5-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-amine 98 (S)-1′-(5-((2-chloropyridin-3-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′- piperidin]-5-amine 99 (S)-4-((5-(5-amino-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)-3-chlorobenzoic acid 100 (S)-1′-(5-((3-(trifluoromethyl)pyrazin-2-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-amine 101 (S)-1′-(5-((3-chloropyridazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[d]pyrimidine- 6,4′-piperidin]-7-amine 102 (S)-4-((5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyrazine-6,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)-3-chlorobenzamide 103 (S)-(1-amino-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-6-yl)dimethylphosphine oxide 104 (S)-1-amino-1′-(6-amino-5-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-5-carboxylic acid 105 ethyl (S)-1-amino-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-5-carboxylate 106 (S)-1′-(5-((3-(morpholinomethyl)phenyl)thio)pyrazin-2-yl)-6-(trifluoromethyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 107 (S)-6-bromo-5-fluoro-1′-(5-((3-(pentafluoro-16-sulfanyl)phenyl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 108 (S)-N-(3-((5-(1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)phenyl)cyclopropanecarboxamide 109 (S)-6-(6-amino-1-bromo-4H,6H-spiro[cyclopenta[c]thiophene-5,4′-piperidin]-1′-yl)-3-(m-tolyl)- 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 110 (S)-2-(1-amino-5,6,7-trifluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-ethylphenyl)-3- methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 111 (R)-1′-(3-(3-(tert-butyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3,4-dihydro-1H- spiro[naphthalene-2,4′-piperidin]-3-amine 112 (S)-2-(3-amino-1,3-dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-1′-yl)-5- (3-isopropylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 113 (S)-1-amino-1′-(3-(3-chloro-2-morpholinopyridin-4-yl)-4-oxo-4,5-dihydro-1H- pyrrolo[3,2-c]pyridin-6-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 114 (S)-1′-(7-(3-chloro-2-(cyclobutylamino)pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-3-amine 115 (S)-1′-(3-(3-chloro-2-(cyclopropylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N6- methyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1,6-diamine 116 (S)-5-amino-1′-(3-(3-chloro-2-(pyrrolidin-1-yl)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2- fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-3-carboxamide 117 1-(4-(6-((S)-4-amino-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-yl)pyrrolidin-3-ol 118 (S)-1′-(3-(3-chloro-2-((cyclopropylmethyl)amino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- N6,N6-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1,6-diamine 119 (S)-1′-(3-(2-amino-6-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-(tert-butyl)-4,6- dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-4-amine 120 (S)-2-chloro-1′-(3-(1,3-dihydroisobenzofuran-5-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-amine 121 (S)-3-chloro-1′-(3-((2-chlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 122 (S)-1′-(3-(3-chloro-2-(ethylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-4-amine 123 (R)-1′-(7-(methyl(pyridin-4-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-3H- spiro[furo[2,3-b]pyridine-2,4′-piperidin]-3-amine 124 (R)-1′-(3-((3-chloropyridin-4-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-6,7- dihydrospiro[cyclopenta[b]pyridine-5,4′-piperidin]-6-amine 125 (S)-2-methoxy-1′-(3-(1-phenylvinyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 126 (R)-1-(3-benzyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[piperidine-4,2′- pyrrolo[2,3-b]pyridin]-3′-amine 127 (S)-(6-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)(phenyl)methanone 128 (4S)-1′-(3-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 129 1-(6-((S)-5-amino-2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1-phenylethan-1-ol 130 (S)-1′-(3-((2,3-dichloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 131 (S)-6-bromo-1′-(3-(5-(3,4-difluorophenyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4- b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 132 (S)-6-amino-2-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(4- cyclopropoxyphenyl)-3-methylpyrimidin-4(3H)-one 133 (S)-N-(1-amino-1′-(4-amino-5-((4-(methylthio)phenyl)thio)-6-oxo-1,6-dihydropyrimidin-2-yl)- 1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)acetamide 134 (S)-2-(1-amino-6-(methylamino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(4- (benzyloxy)phenyl)-3-methylpyrimidin-4(3H)-one 135 (S)-2-(7-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(benzo[d][1,3]dioxol- 4-ylthio)pyrimidin-4(3H)-one 136 4-amino-6-((1S)-1-amino-7-(1-hydroxyethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- (4-(difluoromethoxy)phenyl)-1-methyipyridin-2(1H)-one 137 (S)-1-amino-1′-(4-amino-6-oxo-5-(4-phenoxyphenyl)-1,6-dihydropyridin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile 138 (S)-6-(1-amino-4-hydroxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(4- cyclohexylphenyl)-1-methylpyridin-2(1H)-one 139 (S)-3-([1,1′-biphenyl]-4-yl)-6-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′- yl)pyridin-2(1H)-one 140 (S)-6-amino-2-(1-amino-6-(2-oxopiperidin-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- methyl-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4(3H)-one 141 (S)-1-(1-amino-1′-(4-amino-5-((4-cyanophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2- yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)urea 142 (S)-4-amino-6-(1-amino-6-chloro-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1- methyl-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)pyridin-2(1H)-one 143 (S)-6-(1-amino-6-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(4-(2- methoxyethoxy)phenyl)-1-methylpyridin-2(1H)-one 144 (S)-6-amino-2-(1-amino-6-(piperidine-1-carbonyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)- 3-methyl-5-(quinolin-8-ylthio)pyrimidin-4(3H)-one 145 (S)-6-amino-2-(1-amino-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methyl- 5-((4-nitrophenyl)thio)pyrimidin-4(3H)-one 146 (S)-6-amino-2-(5-amino-3-nitro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-3- methyl-5-(quinolin-8-ylthio)pyrimidin-4(3H)-one 147 (S)-6-(5-amino-3-(4-methylpiperazin-1-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-1-methyl-3-(naphthalen-1-ylthio)pyridin-2(1H)-one 148 (S)-2-(1-amino-6-(1H-pyrrol-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2,2- difluorobenzo[d][1,3]dioxol-4-yl)thio)pyrimidin-4(3H)-one 149 (S)-7-(5-(1-amino-6-(1H-imidazol-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6- (hydroxymethyl)-3-methylpyrazin-2-yl)isoindolin-1-one 150 (S)-3-(1-amino-6-(ethylamino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(1H-indol-5-yl)- 5-methylpyrazine-2-carboxamide 151 (S)-N-(1-amino-1′-(3-bromo-5-(1H-indol-6-yl)-6-methylpyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-6-yl)cyclopropanecarboxamide 152 (S)-4-(6-amino-5-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- methylpyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 153 (S)-3-(1-amino-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methyl-6-(2- oxoindolin-7-yl)pyrazine-2-carbonitrile 154 (S)-N-(5-(1-amino-7-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2- hydroxyethyl)amino)-3-methylpyrazin-2-yl)benzenesulfonamide 155 (S)-1′-(6-methyl-3-(1H-pyrazol-5-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 156 (S)-2-(3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(8- chlorochroman-7-yl)-5-methylpyrazin-2-yl)propan-2-ol 157 (S)-6-chloro-1′-(5-(7-chloro-2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 158 (S)-4-bromo-1′-(5-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 159 (S)-1-amino-1′-(6-cyano-5-(1H-indazol-7-yl)pyrazin-2-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′- piperidine]-6-carboxamide 160 (S)-1′-(5-(1H-indol-3-yl)-6-iodopyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 161 (R)-6-(5-(7′-amino-7′,8′-dihydro-5′H-spiro[piperidine-4,6′-quinolin]-1-yl)-3-vinylpyrazin-2- yl)isoindolin-1-one 162 (R)-1-(4-(5-(6-amino-6,7-dihydrospiro[cyclopenta[b]pyridine-5,4′-piperidin]-1′-yl)-3- ethylpyrazin-2-yl)-3,3-difluoroindolin-1-yl)ethan-1-one 163 (S)-1′-(5-(3-methyl-1H-indazol-6-yl)-6-phenylpyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 164 (S)-1′-(5-(1H-benzo[d][1,2,3]triazol-6-yl)-6-cyclopropylpyrazin-2-yl)-6-((tetrahydro-2H-pyran- 4-yl)oxy)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 165 (S)-1-amino-1′-(3-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 166 (S)-1′-(3-(1H-benzo[d]imidazol-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 167 (S)-1-(6-(1-amino-5-chloro-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one 168 (1-(6-((S)-1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)methanol 169 1-(6-((1S)-1-amino-6-(methylsulfmyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-5-fluoro-1,2,3,4-tetrahydroquinoline-6-carbonitrile 170 (S)-6-chloro-1′-(3-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5-methyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 171 (S)-5-(6-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4- b]pyrazin-3-yl)-N-(2-methoxyethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxamide 172 (S)-1-amino-5-fluoro-1′-(3-(6-(piperazin-1-yl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 173 (S)-2-(1-(6-(1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylic acid 174 (S)-1′-(6-(aminomethyl)-5-(2,3-dichloropyridin-4-yl)pyrazin-2-yl)-6-(1H-imidazol-1-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 175 (1S)-1-amino-1′-(5-(2,3-dichloropyridin-4-yl)-3-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-6- methylpyrazin-2-yl)-N,N-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carboxamide 176 (S)-1′-(8-(2-amino-3-chloropyridin-4-yl)-7-methylimidazo[1,2-c]pyrimidin-5-yl)-5-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 177 (S)-1′-(5-(1-methyl-1H-indol-2-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3,3-d2- 1-amine 178 (S)-1-(6-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one 179 (S)-1′-(3-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine 180 (3-((S)-1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((R)-1- methylisoindolin-2-yl)pyrazin-2-yl)methanol 181 (S)-1′-(3-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5,5-d2-7-amine 182 (S)-4-(difluoromethyl)-1′-(5-methyl-6-((R)-2-methyl-3,4-dihydro-1,5-naphthyridin-1(2H)- yl)pyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 183 (S)-1′-(8-(2-chloro-3-(isopropyl(methyl)amino)phenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)- 2,3,6,8-tetrahydrospiro[indeno[5,6-b][1,4]dioxine-7,4′-piperidin]-6-amine 184 (S)-1-(5-amino-1′-(8-((5-chloro-1-methylindolin-6-yl)thio)imidazo[1,5-a]pyridin-5-yl)-2,3,5,7- tetrahydro-1H-spiro[cyclopenta[b]pyrrolo[3,2-e]pyridine-6,4′-piperidin]-1-yl)ethan-1-one

The present invention further provides a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof as defined herein and at least one pharmaceutically acceptable excipient.

In some embodiments, the compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10.

The present invention additionally provides a combination pharmaceutical product comprising the compound or a pharmaceutically acceptable salt thereof mentioned above, together with one or more other therapeutically active agents.

The present invention further provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product for the preparation of a medicament.

In some embodiments, the medicament is used for the treatment or prevention of cancer, cancer metastasis , cardiovascular disease, an immunological disorder or an ocular disorder.

The present invention additionally provides use, in the manufacture of a medicament for use as an inhibitor of SHP2, of at least one above-mentioned compound or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product.

The present invention further provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product for the preparation of a medicament in the treatment of diseases or conditions mediated by the activity of SHP2.

In some embodiments, wherein the diseases or conditions mediated by the activity of SHP2 is cancer.

In some embodiments, the diseases or conditions mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.

The present invention additionally provides a method for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease, comprising administering to the patient in need thereof a therapeutically effective amount of the above-mentioned compound or the pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product, and the disease is cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.

The present invention further provides a method for inhibiting the activity of SHP2 level, comprising administering to the patient in need thereof a therapeutically effective amount of the above-mentioned compound or the pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product.

The present invention additionally provides a method for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease, comprising administering to the patient in need thereof a therapeutically effective amount of the above-mentioned compound or the pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product, and the disease is mediated by the activity of SHP2.

In some embodiments, the disease mediated by the activity of SHP2 is cancer.

In some embodiments, the disease mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.

The present invention further provides the above-mentioned compound or the pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product for use in preventing or treating a disease, lessening a disease symptom, delaying the progression or onset of a disease, wherein the disease is cancer, cancer metastasis , cardiovascular disease, an immunological disorder or an ocular disorder.

The present invention additionally provides the above-mentioned compound or the pharmaceutically acceptable slat thereof, the above-mentioned pharmaceutical composition , or the above-mentioned combination pharmaceutical product, for use in inhibiting the activity of SHP2.

The present invention further provides the above-mentioned compound or the pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition, or the above-mentioned combination pharmaceutical product for use in preventing or treating a disease, lessening a disease symptom, delaying the progression or onset of a disease, and the disease is mediated by the activity of SHP2.

In some embodiments, the disease mediated by the activity of SHP2 is cancer.

In some embodiments, the disease mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.

Definition

As used herein, the singular form “a”, “an”, and “the” include plural references unless indicated otherwise. For example, “a” substituent includes one or more substituents.

As used herein, the term “alkyl” is defined to include saturated aliphatic hydrocarbons including straight chains and branched chains. In some embodiments, the alkyl group has 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. For example, the term “C₁₋₆ alkyl,” as well as the alkyl moieties of other groups referred to herein (e.g., C₁₋₆ alkoxy) refers to linear or branched radicals of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl). For yet another example, the term “C₁₋₄ alkyl” refers to linear or branched aliphatic hydrocarbon chains of 1 to 4 carbon atoms; the term “C₁₋₃ alkyl” refers to linear or branched aliphatic hydrocarbon chains of 1 to 3 carbon atoms; the term “C₁₋₂ alkyl” refers to methyl and/or ethyl; and the term “C1 alkyl” refers to methyl. An alkyl group optionally can be substituted by one or more (e.g., 1 to 5) suitable substituents.

As used herein, the term “alkoxy” or “alkyloxy” refers to an -0-alkyl group. For example, the term “C_(h6) alkoxy” or “C₁₋₆ alkyloxy” refers to an -0-(C₁₋₆ alkyl) group; and the term “C₁₋₄ alkoxy” or “C₁-₄ alkyloxy” refers to an -0-(C₁₋₄ alkyl) group; For another example, the term “C₁,₂ alkoxy” or “C₁₋₂ alkyloxy” refers to an -0-(C₁₋₂ alkyl) group. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. The alkoxy or alkyloxy group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.

As used herein, the term “Alkylene” refers to a divalent hydrocarbyl group having the specified number of carbon atoms which can link two other groups together. Sometimes it refers to a group -(CH₂)_(t)— where is 1-8, and preferably t is 1-4. Where specified, an alkylene can also be substituted by other groups and may include one or more degrees of unsaturation (i.e., an alkenylene or alkynlene moiety) or rings. The open valences of an alkylene need not be at opposite ends of the chain. Thus branched alkylene groups such as —CH(Me)—, —CH₂CH(Me)— and —C(Me)₂— are also included within the scope of the term “alkylenes” as are cyclic groups such as cyclopropan-1,1-diyl and unsaturated groups such as ethylene (—CH═CH—) or propylene (—CH₂—CH═CH—). Where an alkylene group is described as optionally substituted, the substituents include those typically present on alkyl groups as described herein.

As used herein, the term “halo” or “halogen” refers to fluoro (which may be depicted as —F), chloro (which may be depicted as —Cl), bromo (which may be depicted as —Br), or iodo (which may be depicted as —I). The preferred halogen groups include F, Cl and Br. The terms “haloC₁₋₆alkyl”, “haloC₂₋₆alkenyl”, “haloC₂₋₆alkynyl” and “haloC₁₋₆alkoxy” mean a C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₆alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embiment, preferred are fluoroC₁₋₆alkyl, fluoroC₂₋₆alkenyl, fluoroC₂₋₆alkynyl and fluoroC₁₋₆alkoxy groups, in particular fluoroC₁₋₃alkyl, for example, CF₃, CHF₂, CH₂F, CH₂CH₂F, CH₂CHF₂, CH₂CF₃ and fluoroC₁₋₃alkoxy groups, for example, OCF₃, OCHF₂, OCH₂F, OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, and most especially CF₃, OCF₃ and OCHF₂.

As used herein, the term “n-membered”, where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual sub-combination of the members of such groups and ranges. For example, the term “C₁₋₆ alkyl” is specifically intended to include C₁ alkyl (methyl), C₂ alkyl (ethyl), C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl. For another example, the term “a 5- to 12-membered heteroaryl group” is specifically intended to include any 5—, 6—, 7—, 8—, 9—, 10—, 11- or 12-membered heteroaryl group.

As used herein, the term “oxo” refers to ═O. When an oxo is substituted on a carbon atom, they together form a carbonyl moiety [—C(═O)—]. When an oxo is substituted on a sulfur atom, they together form a sulfinyl moiety [—S(═O)—]; when two oxo groups are substituted on a sulfur atom, they together form a sulfonyl moiety [—S(═O)₂—].

As used herein, the term “aryl” or “aromatic” refers to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having the well-known characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron system. Typically, aryl groups contain 6 to 20 carbon atoms (“C₆—C₂₀ aryl”) as ring members, preferably 6 to 14 carbon atoms (“C₆—C₁₄ aryl”) or more preferably, 6 to 12 carbon atoms (“C₆—C₁₂ aryl”). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl or heteroaryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided the point of attachment to the base molecule on such fused ring systems is an atom of the aromatic portion of the ring system. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group is unsubstituted or substituted as further described herein.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to monocyclic or fused bicyclic or polycyclic ring systems having the well-known characteristics of aromaticity that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in an aromatic ring. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as 6-membered rings. Typically, heteroaryl groups contain 5 to 20 ring atoms (“5-20 membered heteroaryl”), preferably 5 to 14 ring atoms (“5-14 membered heteroaryl”), and more preferably 5 to 12 ring atoms (“5-12 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained. Thus, 6-membered heteroaryl rings may be attached to the base molecule via a ring C atom, while 5-membered heteroaryl rings may be attached to the base molecule via a ring C or N atom. Heteroaryl groups may also be fused to another aryl or heteroaryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided the point of attachment to the base molecule on such fused ring systems is an atom of the heteroaromatic portion of the ring system. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, indazole,

quinoline, isoquinoline, purine, triazine, naphthryidine and carbazole. In frequent preferred embodiments, 5- or 6-membered heteroaryl groups are selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl, pyrazinyl or pyridazinyl rings. The heteroaryl group is unsubstituted or substituted as further described herein.

As used herein, the term “heterocyclyl”, “heterocyclic” or “heteroalicyclic” used interchangeably herein refers to a non-aromatic, saturated or partially unsaturated ring system containing the specified number of ring atoms, including at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)_(x), where x is 0, 1 or 2) and where the heterocyclic ring is connected to the base molecule via a ring atom, which may be C or N. Heterocyclic rings include rings which are spirocyclic, bridged, or fused to one or more other heterocyclic or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocyclic portion of the ring system. Preferably, heterocyclic rings contain 1 to 4 heteroatoms selected from N, O, and S(O)_(q) as ring members, and more preferably 1 to 2 ring heteroatoms, provided that such heterocyclic rings do not contain two contiguous oxygen atoms. Heterocyclyl groups are unsubstituted or substituted by suitable substituent groups, for example the same groups that are described herein as suitable for alkyl, aryl or heteroaryl. Such substituents may be present on the heterocycylic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto. In addition, ring N atoms are optionally substituted by groups suitable for an amine, e.g., alkyl, acyl, carbamoyl, sulfonyl substituents, and the like.

As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated or partially unsaturated carbocyclic ring system containing the specified number of carbon atoms, which may be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups of the invention contain 3 to 12 carbon atoms (“C₃—C₁₂ cycloalkyl”), preferably 3 to 8 carbon atoms (“C₃—C₈ cycloalkyl”). Representative examples include, e.g., cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, adamantane, and the like. Cycloalkyl groups are unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

Compounds described herein can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention. In some embodiments, one or more hydrogen atoms of any of the compounds described herein can be substituted with deuterium to provide the corresponding deuterium-labeled or -enriched compounds.

The term “composition”, as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.

“SHP2” means “Src Homolgy-2 phosphatase” and is also known as SH-PTP2, SH-PTP3, Syp, PTP1D, PTP2C, SAP-2 or PTPN11.

Cancers harboring “PTPNll mutations” include but are not limited to: N58Y, D61Y, V; E69K; A72V, T, D; E76G, Q, K (ALL); G60A: D61Y; E69V; F71K; A72V; T731; E76G, K; R₂₈₉G; G503V (AML); G6OR, D61Y, V, N; Y₆₂D; E69K; A72T, V; T731; E76K, V, G, A, Q; E139D; G503A, R; Q506P (JMML); G60V; D61V; E69K; F71L; A72V; E76A (MDS), Y₆₃C (CMML); Y₆₂C; E69K; T507K (neuroblastoma); V46L; N58S; E76V (Lung cancer), R₁₃₈Q (melanoma); E76G (colon cancer).

The term “subject” (alternatively referred to herein as “patient”) as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of Formula I, II, III or IV are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).

The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts”. The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.

The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.

The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

When a tautomer of the compound of Formula (I) exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.

When the compound of Formula (I) and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of Formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).

The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds represented by Formula I, or a prodrug, or a metabolite, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt % to about 1 Owt % of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

Generally, dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

These and other aspects will become apparent from the following written description of the invention.

EXAMPLES

The following Examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:

DMF N,N-Dimethylformamide EA Ethyl acetate Hex Hexane MeOH Methanol DCM Dichloromethane DCE 1,2-Dichloroethane EtOH Ethanol t-BuOH tert-Butanol iPrOH Propan-2-ol CD₃I Iodomethane-d3 LiHMDS Lithium bis(trimethylsilyl)amide THF Tetrahydrofuran Ti(OEt)₄ Titanium ethoxide NMP 1-Methyl-2-pyrrolidinone DIPEA N,N-Diisopropylethylamine (Boc)₂O Di-tert-butyl dicarbonate LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide PPA Polyphosphoric acids TEA Triethylamine PPh₃ Triphenylphosphane Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene BINAP 2,2′-Bis(diphenylphosphanyl)-1,1′-binaphthalene DavePhos 2′-(dicyclohexylphosphanyl)-N,N-dimethyl-[1,1′-biphenyl]-2-amine Pd(OAc)₂ Palladium diacetate Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl₂•CH₂Cl₂ [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex BOP Benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate PyBOP Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate K₄Fe(CN)₆•3H₂O Potassium ferrocyanide trihyrate Cy₃PH•BF₄ Tricyclohexylphosphonium tetrafluoroborate t-BuOK Potassium tert-butoxide NaOEt Sodium ethoxide NCS N-Chlorosuccinimide NBS N-Bromosuccinimide NIS N-Iodosuccinimide TFA 2,2,2-Trifluoroacetic acid RT Room temperature min minute(s) h hour(s) aq aqueous sat saturated TLC Thin layer chromatography Prep - TLC Preparative thin layer chromatography

Intermediate A1

A mixture of 3-chloro-4-iodopyridin-2-amine (25.55 g, 100.41 mmol), methyl 3-mercaptopropanoate (12.72 g, 105.85 mmol), Pd₂(dba)₃ (0.96 g, 1.05 mmol), XantPhos (1.21 g, 2.09 mmol) and DIPEA (26.01 g, 201.25 mmol) in 1,4-dioxane (80 mL) was stirred for 18 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA (80 mL), filtered and concentrated under reduced pressure. The residue was diluted with EA (50 mL) and Hex (250 mL), the resulting suspension was stirred for 10 min and filtered. The filter cake was collected. The filtration was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluting with EA:Hex=1:1, v/v). The product was combined with the filter cake to give compound A1-1 (21.62 g). MS: 247 [M+1]⁺.

Sodium (2.48 g, 107.83 mmol) was dissolved in EtOH (200 mL) and added to a suspension of compound A1-1 (21.62 g, 87.63 mmol) in EtOH (100 mL) dropwise at 0° C. The resulting mixture was allowed to warm to RT and stirred for 2 h. The mixture was diluted with EtOH (20 mL) and DCM (200 mL), stirred for another 20 min, filtered and washed with DCM (30 mL). The filter cake was collected and dried in an high vacuum oven to afford intermediate A1 (12.72 g). MS: 161 [M−Na+2H]⁺.

The following compounds were synthesized using the above procedure with the corresponding starting materials.

Intermediate A2

To a −80° C. solution of 2,6-dibromonaphthalene (994 mg, 3.48 mmol) in THF (20 mL) under nitrogen atmosphere was added n-BuLi (2.5 M, 1.60 mL, 4.00 mmol) dropwise. The resulting mixture was stirred for 50 min at −80° C. Then triisopropyl borate (789 mg, 4.20 mmol) was added and the resulting mixture was allowed to warm to RT and stirred for 16 h. Hydrochloric acid (1 M, 10.00 mL) was added and stirred for 1 h. The reaction mixture was diluted with brine. The layers were separated and the organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give intermediate A2 (922 mg) as an off—white solid.

The following compound was synthesized using the above procedure with 2-bromo-5-chlorothiophene.

Intermediate B1

To a 0° C. mixture of 3-bromo-6-chloropyrazin-2-amine (511 mg, 2.45 mmol) in DMF (5 mL) under nitrogen atmosphere was added NaH (60%, 153 mg, 3.83 mmol). The resulting mixture was allowed to warm to RT and stirred for 30 min. Then CH₃I (453 mg, 3.19 mmol) was added and the resulting mixture was stirred for 1 h at RT. The reaction mixture was quenched with brine (50 mL) and extracted with EA (80 mL). The organic layer was washed with brine (3×50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give intermediate B1 (503 mg) as a brown solid which was used in next step without further purification. MS: 222 [M+1]⁺.

The following compounds were synthesized using with corresponding starting materials.

Intermediate B2

A mixture of 6-chloropyridin-2(1H)-one (5.03 g, 38.83 mmol), CH₃I (8.49 g, 66.86 mmol), K₂CO₃ (8.99 g, 65.05 mmol) and EtOH (25 mL) in a sealed tube was stirred for 17 h at 70° C. After cooling to RT, the reaction mixture was poured into water (200 mL) and extracted with EA (2 A 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound B2-1 (4.35 g) as a yellow solid. MS: 144 [M+1]⁺. Following procedures of WO 2007146824, intermediate B2 was prepared from compound B2-1.

Intermediate C1

To a −70° C. solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (26.02 g, 101.18 mmol) in THF (100 mL) under nitrogen atmosphere was added LDA (2 M, 65.00 mL, 130.00 mmol) dropwise. The resulting mixture was stirred for 1 h at -70° C. Then (bromomethyl)benzene (17.98 g, 105.12 mmol) was added and the resulting mixture was stirred for 30 min. The reaction mixture was quenched by the addition of brine (100 mL) dropwise. The layers were separated and the organic layer was washed with brine (1×80 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound C1-1 (38.05 g, crude) as a yellow oil. MS: 348 [M+1]⁺.

A mixture of compound C1-1 (38.05 g, 0.11 mol) and PPA (50.00 g) was stirred for 1.5 hat 130° C. After cooling to RT, the reaction mixture was poured into ice/water and the pH value of the resulting mixture was adjusted to 9 with NaOH. (Boc)₂O (40.12 g, 0.18 mol) was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was extracted with EA (3×150 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give compound C1-2 (10.00 g). MS: 302 [M+1]⁺.

A mixture of compound C1-2 (10.00 g, 0.033 mol) and (R)-(+)-2-methyl-2-propanesulfinamide (8.33 g, 0.069 mol) in Ti(OEt)₄ (50 mL) was stirred for 2 h at 120° C. The reaction mixture was poured into water (100 mL) and diluted with EA (300 mL). The resulting mixture was filtered through a pad of Celite, the filtrate was separated and the organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound C₁₋₃ (18.49 g, crude) as a yellow oil. MS: 405 [M+1]⁺.

To a −50° C. solution of compound C₁₋₃ (18.49 g, 0.046 mol) in THF (100 mL) was added BH₃ /THF (1 M, 125.00 mL, 0.13 mol) dropwise. The resulting mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was quenched by the addition of brine dropwise. The layers were separated and the organic layer was washed with brine (1×100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound C1-4 (8.06 g) as a yellow oil. MS: 407 [M+1]⁺.

A mixture of compound C1-4 (8.06 g, 0.020 mol) and HCl/EA (4 M, 20.00 mL, 80.00 mmol) in DCM (120 mL) was stirred for 1 h at RT. Another portion of HCl/EA (4 M, 10.00 mL, 40.00 mmol) was added and stirred for 1.5 h at RT. The reaction mixture was filtered followed by EA (50 mL) wash. The filter cake was collected, dried under high vacuum to give intermediate C1 (4.57 g) as a white solid. MS: 203 [M+1]⁺.

The following compounds were synthesized using the above procedure or modified procedure with the corresponding starting materials.

Intermediate C2

A solution of 2,2′-azanediylbis(ethan-l-ol) (198.15 g, 1.88 mol), K₂CO₃ (520.95 g, 3.77 mol) and (bromomethyl)benzene (386.79 g, 2.26 mol) in acetonitrile (2000 mL) was stirred at 90° C. for 2.5 h. After cooling to RT, the reaction mixture was filtered followed by EA (2×100mL) wash. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:10, v/v) to give compound C2-1 (89.44 g) as a colorless oil. MS: 196 [M+H]⁺.

To a 0° C. solution of compound C2-1 (30.66 g, 0.16 mol) in toluene (300 mL) was added tribromophosphane (69.13 g, 0.26 mol) dropwise. The resulting mixture was stirred at 105° C. for 16 h. After cooling to RT, the volatiles were removed under reduce pressure. The residue was diluted with water (300 mL), and the pH value was adjusted to 9 with NaOH. The resulting mixture was extracted with EA (3×150 mL), the organic layers combined, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give compound C2-2 (41.58 g) which was used in next step without any further purification. MS: 320 [M+H]⁺.

To a 0° C. solution of compound C2-2 (1.70 g, 12.77 mmol) in DMF (20 mL) under nitrogen atmosphere was added NaH (60% dispersion in mineral oil, 982 mg, 24.55 mmol) in three portions, and the mixture was heated to 60° C., stirred for 1 h at this temperature. Then N-benzyl-2-bromo-N-(2-bromoethypethan-l-amine (4.54 g, 14.14 mmol) was added and stirred at 60° C. for another 1 h. After cooling to RT, the reaction mixture was quenched with water (80 mL), extracted with EA (3×80 mL). The combined organic layers were washed with water (3×80 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give compound C2-3 (1.14 g). MS: 293 [M+H]⁺.

To a 0° C. solution of compound C2-3 (1.05 g, 3.59 mmol) in DCE (10 mL) was added 1-chloroethyl carbonochloridate (903 mg, 6.32 mmol) dropwise. The resulting mixture was stirred at RT for 1.5 h. The volatiles were removed under reduced pressure and the residue was dissolved in MeOH (20 mL), stirred at 80° C. for 4 h. The volatiles were removed under reduced pressure and dissolved in DCM (20 mL). DIPEA (1.33 g, 10.32 mmol) and (Boc)₂O (1.38 g, 6.32 mmol) were added. The resulting solution was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:1, v/v) to give compound C2-4 (438 mg). MS: 303 [M+H]⁺.

Intermediate C2 was synthesized in the manner similar to intermediate C1, except compound C1-2 was replaced with compound C2-4.

Intermediate C3

To a -78° C. solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (2.83 g, 11.00 mmol) in THF (50 mL) was added LDA (2 M, 6.00 mL, 12.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 1 h at this temperature. Then 2-chloro-5-(chloromethyl)thiazole (in 3 mL THF, 1.69 g, 10.06 mmol) was added dropwise and stirred for 1 h. The reaction mixture was quenched with brine (50 mL), extracted with EA (2×30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:20, v/v) to give compound C3-1 (1.15 g). MS: 389 [M+H]⁺.

To a −78° C. solution of compound C3-1 (900 mg, 2.31 mmol) in THF (50 mL) was added LDA (2 M, 3.00 mL, 6.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 30 min at this temperature, and quenched with brine (30 mL). The resulting mixture was extracted with EA (2×30 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound C3-2 (832 mg). MS: 343 [M+1]⁺.

Compound C3-4 was synthesized in the manner similar to intermediate C1-4, except compound C1-2 was replaced with compound C3-2.

A suspension of compound C3-4 (2.50 g, 5.58 mmol), TEA (2 mL) and Pd/C (10%, 690 mg) in MeOH (50 mL) was stirred for 24 h at 40° C. under hydrogen atmosphere. The resulting mixture was filtered, and an additional portion of Pd/C (10%, 1.32 g) was added to the filtration. The resulting mixture was stirred for another 16 h at 50° C. under hydrogen atmosphere. The resulting mixture was filtered, the filtration was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:1, v/v) to give intermediate C3 (1.28 g). MS: 414 [M+H]⁺.

Intermediate C4

To a −30° C. solution of compound C1-4 (695 mg, 1.71 mmol) in DMF (6 mL) was added LiHMDS (1 M, 2.10 mL, 2.10 mmol) dropwise. The resulting mixture was stirred for 1.5 h at this temperature. Then CH₃I (496 mg, 3.49 mmol) was added dropwise. The resulting mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (EA:Hex=2:5, v/v) to give compound C4-1 (232 mg) as a yellow solid. MS: 421 [M+1]⁺.

A mixture of compound C4-1 (232 mg, 0.55 mmol) and HCl/EA (4 M, 2.00 mL, 8.00 mmol) in EA (5 mL) was stirred for 1.5 h at RT. The reaction mixture was filtered. The filter cake was collected, dried under high vacuum to give intermediate C4 (50 mg) as a white solid. MS: 217 [M+1]⁺.

Following procedures of WO2018172984, the following intermediates were prepared with corresponding starting materials.

Intermediate C5

To a solution of 2,3-dibromopyridine (47.38 g, 0.20 mol) in THF (300 ml) was added isopropylmagnesium chloride (2 M solution in THF, 110 mL) dropwise at RT under nitrogen atmosphere. The reaction mixture was stirred for 1.5 h, and C5-1 (46.93 g in 130 mL THF, 0.22 mol) was added at RT. The reaction mixture was stirred for 1 h and quenched with brine (300 mL), and then the mixture was filtered. The filtrate was separated and the organic layer was collected. The aqueous layer was extracted with EA (1×200 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give C5-2 (87.67 g) which was used without any further purification. MS: 371 (M+H)⁺.

To a solution of C5-2 (64.77 g, 17.45 mmol) in DCM (500 mL) was added Dess-Martin (90.12 g, 21.25 mmol) below 30° C. The resulting mixture was stirred for 4 h, and then saturated sodium bicarbonate solution (500 mL) and saturated sodium carbonate solution (300 mL) were added. The organic layer was collected and washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was added to the solution of EA (60 mL) and Hex (300 mL) and stirred for 27 h. The mixture was filtered, and the filter cake was collected to give C5-3 (30.57 g) as an off-white solid. MS: 369 (M+H) +.

To a −30° C. solution of C5-3 (10.16 g, 27.52 mmol) in THF (80 mL) were added LiHMDS (1 M solution in THF, 31.00 mL) and CD₃I under nitrogen atmosphere. The resulting mixture was allowed to warm to RT and stirred for 20 h. The reaction mixture was quenched with brine (80 mL), and the organic layer was collected. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA:Hex=1:5, v/v) to give C5-4 (8.40 g). MS: 386 (M+H)⁺.

A mixture of C5-4 (8.40 g, 21.74 mmol), Cs₂CO₃ (7.04 g, 21.61 mmol), pivalic_(.)ucid (672 mg, 6.58 mmol), Pd(OAc)₂ (248 mg, 1.10 mmol) and Cy₃PHBF₄ (809 mg, 2.20 mmol) in 1,3,5-mesitylene (40 mL) was stirred for 16 h at 140° C. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA:Hex=1:1, v/v) to give C5-5 (3.80 g). MS:305 (M+H) +.

A mixture of C5-5 (3.80 g, 12.48 mmol) and (R)-(+)-2-Methyl-2-propanesulfinamide (3.03 g, 25.00 mmol) in Ti(OEt)₄ (38 mL) was stirred for 2 h at 100° C. After cooling to RT, the reaction mixture was diluted with EA (200 mL) and water (40 mL). The resulting mixture was filtered through a pad of Celite followed by EA (40 mL) wash. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give C5-6 (5.50 g). MS: 408 (M+H) +.

To a −40° C. solution of C5-6 (5.40 g, 13.25 mmol) in THF (50 mL) was added BH₃ (1 M solution in THF, 40.00 mL). The resulting mixture was allowed to warm to RT and stirred for 3 h. The reaction mixture was quenched with MeOH (150 mL) and stirred at 80° C. for 20 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA:Hex=1:1, v/v) to give C5-7 (3.78 g). MS: 410 (M+H) +.

To solution of C5-7 (3.70 g, 9.03 mmol) in EA (40 mL) was added HCl (4 M solution in EA, 15 mL), and stirred at RT for 17 h. The resulting mixture was filtered followed by EA (10 *2 mL) wash, and then the filter cake was concentrated under reduced pressure to give C5 (3.30 g) as a white solid. MS: 206 (M+H)⁺.

Examnle 1

A solution of propane-1,2-diamine (11.00 mL, 129.11 mmol) in EtOH (220 mL) was cooled to 0° C. Diethyl 2-oxomalonate (20.00 mL, 131.15 mmol) was added to the solution dropwise. Then the cooling bath was removed. The solution was allowed to warmed to RT and stirred for 1 h. The clear solution had become a thick mixture. The mixture was warmed to reflux temperature and stirred for 24 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give compound 1-1 (27.12 g, crude) as a solid. MS: 183 [M+1]⁺.

To a 0° C. solution of compound 1-1 (27.12 g, crude) in DMF (100 mL) under nitrogen atmosphere was added NBS (21.30 g, 0.12 mol). The resulting mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was diluted with brine (100 mL) and EA (400 mL). The organic layer was separated, washed with water (2×100 mL) and brine (3×100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:100, v/v) to give compound 1-2 (7.75 g) as a yellow solid. MS: 261 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ12.72 (brs, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.44 (s, 3H), 1.28 (t, J=7.1 Hz, 1H).

To a solution of PPh₃ (31.03 g, 80.18 mmol) in 1,4-dioxane (280 mL) was added NCS (10.77 g, 80.66 mmol). The resulting mixture was stirred for 30 min at RT. Compound 1-2 (6.96 g, 26.66 mmol) was added, the resulting mixture was warmed to 100° C. and stirred for 1 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:5, v/v) to give compound 1-3 (6.66 g) as a yellow oil. MS: 279 [M+1]⁺.

A mixture of compound 1-3 (1.19 g, 4.26 mmol), (2,3-dichlorophenyl)boronic acid (1.21 g, 6.34 K₂CO₃ (2.42 g, 17.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.44 g, 0.54 mmol) in CH₃CN/H₂O (15 mL/1 mL) was stirred for 2.5 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA (50 mL) and washed with brine (2×50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:30, v/v) to give compound 1-4 (0.67 g). MS: 345 [M+1]⁺.

A mixture of compound 1-4 (0.67 g, 1.94 mmol), intermediate Cl (0.64 g, 2.33 mmol) and K₂CO₃ (2.70 g, 19.54 mmol) in CH₃CN (15 mL) was stirred for 24 h at 100° C. After cooling to RT, the reaction mixture was diluted with EA (60 mL) and water (100 mL). The organic layer was separated, the aqueous layer was extracted with EA (1×50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:50, v/v) to give example 1 (468 mg) as a yellow solid. MS: 511 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ7.65 (dd, J=7.9, 1.6 Hz, 1H), 7.47-7.34 (m, 3H), 7.29-7.14 (m, 3H), 4.40 (q, J=7.1 Hz, 2H), 4.02-3.91 (m, 3H), 3.41-3.37 (m, 1H), 3.32-3.30 (m, 1H), 3.19-3.15 (m, 1H), 2.85-2.81 (m, 1H), 2.27 (s, 3H), 1.94-1.82 (m, 2H), 1.62-1.55 (m, 1H), 1.46 (m, 1H), 1.39 (t, J=7.1 Hz, 3H).

The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

Ex No. Chemical Name Structure MS & ¹HNMR 2 (S)-1′-(5-(2,3- dichlorophenyl)-6- methylpyrazin-2-yl)-5,7- dihydrospiro[cyclo- penta[b]pyridine-6,4′- piperidin]-5-amine

MS: 440 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.34 (d, J = 4.6 Hz, 1H), 8.05 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.0, 1.5 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.32-7.25 (m, 2H), 4.38-4.33 (m, 2H), 4.03 (s, 1H), 3.29-3.22 (m, 3H), 2.96-2.90 (m, 1H), 2.19 (s, 3H), 1.96- 1.80 (m, 2H), 1.68-1.62 (m, 1H), 1.46- 1.39 (m, 1H).

Example 3

A mixture of example 1 (302 mg, 0.59 mmol) and LiOH (81 mg, 3.38 mmol) in MeOH/H₂(20 mL/3 mL) was stirred for 4 h at 60° C. After cooling to RT, MeOH was removed under reduced pressure. The residue was dissolved in brine (50 mL), extracted with EA (3×40 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give example 3 (258 mg) as a light yellow solid. MS: 483 [M+1]⁺.

Example 4

A solution of example 3 (60 mg, 0.12 mmol), (Boc)₂O (0.50 mL, 2.18 mmol) and DIPEA (1.00 mL, 6.05 mmol) in DCM was stirred for 1 h at 40° C. The reaction solution was concentrated under reduced pressure to give compound 4-1 (0.39 g, crude), which was used in next step without further purification. MS: 583 [M+1]⁺.

A solution of compound 4-1 (0.39 g, crude), NH₄Cl (466 mg, 8.71 mmol), PyBOP (194 mg, 0.37 mmol) and DIPEA (0.50 mL, 3.03 mmol) in NMP (8 mL) was stirred for 2 h at 80° C. The reaction solution was diluted with EA (40 mL) and washed with brine (3×30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 4-2 (0.37 g, crude) as a yellow oil, which was used in next step without further purification. MS: 582 [M+1]⁺.

A mixture of compound 4-2 (0.37 g, crude) and HCl/EA (4 M, 3.00 mL, 12.00 mmol) in DCM (20 mL) was stirred for 2.5 h at RT. The reaction mixture was diluted with brine (50 mL) and the pH value was taken to 9 with NH₃H₂O (25%). The resulting mixture was extracted with DCM (1×50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:10, v/v) to give example 4 (9 mg) as a light yellow solid. MS: 482 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ7.66 (d, J=9.4 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.48-7.29 (m, 5H), 4.39 (s, 1H), 4.13-4.00 (m, 2H), 3.39-3.35 (m, 1H), 3.31-3.28 (m, 1H), 3.24-3.12 (m, 2H), 2.29 (s, 3H), 2.03-1.88 (m, 2H), 1.73-1.62 (m, 2H).

Example 5

A mixture of intermediate A1 (504 mg, 2.76 mmol), compound 1-3 (769 mg, 2.75 mmol), Pd₂(dba)₃ (127 mg, 0.14 mmol), XantPhos (144 mg, 0.25 mmol) and DIPEA (1.10 g, 8.51 mmol) in 1,4-dioxane (20 mL) was stirred for 3 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was quenched with brine (100 mL), extracted with EA (1×60 mL), the organic layer dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound 5-1 (489 mg) as a yellow solid. MS: 359 [M+1]⁺.

Example 5 was synthesized in the manner similar to example 1, except compound 1-4 was replaced with compound 5-1. MS: 525 1M+11⁺. ¹HNMR (400 MHz, methanol-d₄) δ7.63 (d, J=5.5 Hz, 1H), 7.47-7.34 (m, 1H), 7.26-7.19 (m, 3H), 5.91 (d, J=5.5 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 4.06-3.98 (m, 2H), 3.97 (s, 1H), 3.43-3.35 (m, 2H), 3.18-3.14 (m, 1H), 2.85-2.81 (m, 1H), 2.49 (s, 3H), 1.96-1.76 (m, 2H), 1.64-1.57 (m, 1H), 1.48-1.42 (m, 1H), 1.39 (t, J=8.0 Hz, 3H).

The following examples were synthesized using the above procedure or modified procedure with the corresponding starting materials.

EX No Chemical Name Structure MS & ¹HNMR 6 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)-6-methyl- pyrazin-2-yl)-1,3-di- hydrospiro[indene-2,4′- piperidin]-1-amine

MS: 453 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.16 (s, 1H), 7.60- 7.32 (m, 5H), 5.80 (s, 1H), 4.46-4.25 (m, 3H), 3.46-3.35 (m, 2H), 3.23- 3.08 (m, 2H), 2.45 (s, 3H), 1.89-1.57 (m, 4H). 7 (S)-1′-(6-amino-5- ((2,3-dichlorophenyl) thio)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyridine- 6,4′-piperidin]-5- amine

MS: 473 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.36 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.62 (s, 1H), 7.37-7.22 (m, 2H), 7.13 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.33 (d, J = 13.4 Hz, 2H), 4.05 (s, 1H), 3.29-3.17 (m, 3H), 2.94 (d, J = 16.5 Hz, 1H), 1.98-1.75 (m, 2H), 1.70- 1.57 (m, 1H), 1.48-1.37 (m, 1H). 8 (S)-1′-(4-amino-5- ((2-amino-3-chloro- pyridin-4-yl)thio) pyrimidin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′- piperidin]-5-amine

MS: 455 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.41 (d, J = 4.4 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 5.5 Hz, 1H), 7.31 (dd, J = 7.6, 5.2 Hz, 1H), 6.03 (d, J = 5.5 Hz, 1H), 4.62 (t, J = 13.3 Hz, 2H), 4.19 (s, 1H), 3.24 (m, 3H), 3.09-2.95 (m, 1H), 1.92-1.63 (m, 2H), 1.63- 1.42 (m, 2H). 9 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)pyridin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyridine- 6,4′-piperidin]-5- amine

MS: 439 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.38 (d, J = 4.5 Hz, 1H), 8.21 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.72-7.55 (m, 2H), 7.38-7.26 (m, 1H), 6.97 (d, J = 9.0 Hz, 1H), 5.92 (d, J = 5.5 Hz, 1H), 4.43-4.26 (m, 2H), 4.10 (s, 1H), 3.32-3.19 (m, 3H), 3.03-2.91 (m, 1H), 1.98-1.79 (m, 2H), 1.70-1.60 (m, 1H), 1.54-1.44 (m, 1H). 10 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)-6-(methyl- amino)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyridine- 6,4′-piperidin]-5- amine

MS: 469 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.36 (d, J = 4.3 Hz, 1H), 7.83 (d, J = 10.6 Hz, 1H), 7.73- 7.71,7.51-7.49 (m, 1H), 7.59 (dd, J = 9.9, 4.4 Hz, 1H), 7.29 (dd, J = 7.4, 5.2 Hz, 1H), 5.89-5.84 (m, 1H), 4.45- 4.13 (m, 2H), 4.06 (s, 1H), 3.31-3.13 (m, 3H), 3.07 (s, 1H), 2.88 (s, 3H), 2.00-1.77 (m, 2H), 1.67-1.63 (m, 1H), 1.47-1.43 (m, 1H). 11 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)-6-(dimethyl- amino)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyri- dine-6,4′-piperidin]- 5-amine

MS: 483 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.36 (d, J = 4.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.72- 7.50 (m, 1H), 7.64-7.57 (m, 1H), 7.29 (dd, J = 7.5, 5.2 Hz, 1H), 5.89- 5.84 (m, 1H), 4.36 (t, J = 15.0 Hz, 2H), 4.07 (s, 1H), 3.31-3.16 (m, 3H), 3.10 (s, 3H), 3.06 (s, 1H), 2.88 (s, 3H), 1.98-1.77 (m, 2H), 1.71-1.57 (m, 1H), 1.71-1.44 (m, 1H). 12 (S)-1′-(6-amino-5- (thiazol-4-ylthio)pyr- azin-2-yl)-5,7-dihy- drospiro[cyclopenta [b]pyridine-6,4′-pi- peridin]-5-amine

MS: 412 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 9.00 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 4.3 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.53 (s, 1H), 7.40- 7.34 (m, 1H), 7.20 (d, J = 2.0 Hz, 1H), 4.40-4.23 (m, 3H), 3.28-3.06 (m, 4H), 1.90-1.79 (m, 2H), 1.68-1.56 (m, 2H). 13 (S)-1′-(6-amino-5- (thiazol-2-ylthio)pyr- azin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′-pi- peridin]-5-amine

MS: 412 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.41 (d, J = 4.7 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 3.4 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J = 3.4 Hz, 1H), 7.32 (dd, J = 7.5, 5.2 Hz, 1H), 4.45-4.29 (m, 2H), 4.17 (s, 1H), 3.31-3.20 (m, 3H), 3.08-2.96 (m, 1H), 1.97-1.78 (m, 2H), 1.70- 1.59 (m, 1H), 1.55-1.44 (m, 1H). 14 (S)-1′-(6-amino-5- (quinolin-3-ylthio) pyrazin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′- piperidin]-5-amine

MS: 456 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.69 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 4.6 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 7.1 Hz, 2H), 7.33 (dd, J = 7.4, 5.2 Hz, 1H), 4.34 (t, J = 11.8 Hz, 2H), 4.17 (s, 1H), 3.30-3.19 (m, 3H), 3.08-2.95 (m, 1H), 1.92-1.82 (m, 2H) , 1.64 (d, J = 12.5 Hz, 1H), 1.51 (d, J = 12.2 Hz, 1H). 15 (S)-5-amino-1′-(5- ((2-amino-3-chloro- pyridin-4-yl)thio)pyr- idin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′-pi- peridine]-3-carboni- trile

MS: 464 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.20 (d, J = 2.3 Hz, 1H), 7.74 (s, 1H), 7.67-7.56 (m, 2H), 7.45 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 5.91 (d, J = 5.6 Hz, 1H), 4.37-4.27 (m, 2H), 4.07 (s, 1H), 3.29- 3.19 (m, 3H), 2.98-2.93 (m, 1H), 1.95-1.85 (m, 2H), 1.79-1.74 (m, 1H), 1.63-1.60 (m, 1H). 16 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)pyrazin-2-yl)- N-methyl-1,3-di- hydrospiro[indene- 2,4′-piperidin]-1- amine

MS: 453 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.36 (s, 1H), 8.31 (s, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.38-7.21 (m, 3H), 5.96 (d, J = 5.6 Hz, 1H), 4.37-4.27 (m, 1H), 4.25-4.16 (m, 1H), 3.86 (s, 1H), 3.53-3.39 (m, 2H), 3.09 (dd, J = 38.1, 15.9 Hz, 2H), 2.56 (s, 3H), 2.00- 1.92 (m, 1H),1.60-1.51 (m, 2H), 1.37-1.29 (m, 1H). 17 (S)-1′-(5-((3,5-dichloro- pyridin-4-yl)thio) pyrazin-2-yl)-5,6, 7-trifluoro-1,3-di- hydrospiro[indene-2, 4′-piperidin]-1-amine

MS: 512 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.54 (s, 2H), 8.19- 8.05 (m, 2H), 7.06-6.97 (m, 1H), 4.33-3.97 (m, 3H), 3.46-3.34 (m, 2H), 3.09 (d, J = 16.3 Hz, 1H), 2.90 (d, J = 16.2 Hz, 1H), 1.95-1.84 (m, 1H), 1.76-1.60 (m, 2H), 1.59-1.46 (m, 1H). 18 (S)-1-amino-1′-(2- ((2-cyanopyridin-3- yl)thio)pyrimidin-5- yl)-1,3-dihydrospiro [indene-2,4′-piper- idine]-4-carbonitrile

MS: 440 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.52 (s, 2H), 7.87- 7.82 (m, 2H), 7.80-7.76 (m, 2H), 7.56-7.52 (m, 2H), 3.91-3.68 (m, 3H), 3.28-3.08 (m, 4H), 1.86-1.78 (m, 2H), 1.76-1.63 (m, 2H). 19 (S)-1′-(5-((3-chloro- 2-methoxypyridin- 4-yl)thio)pyrazin-2- yl)-6-(methylthio)- 1,3-dihydrospiro [indene-2,4′-piperidin]- 1-amine

MS: 500 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.30 (s, 1H), 8.26 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 4.43 (d, J = 13.8 Hz, 1H), 4.31 (d, J = 13.9 Hz, 1H), 4.13 (s, 1H), 3.28- 3.21 (m, 1H), 3.11 (dd, J = 33.5, 15.9 Hz, 3H), 2.60 (s, 3H), 1.94-1.74 (m, 4H), 1.40 (s, 9H). 20 (S)-1-(5-((5-(4-amino- 2-(tert-butyl)-4, 6-dihydrospiro[cyclo- penta[b]thiophene- 5,4′-piperidin]-1′- yl)pyrazin-2-yl)thio)- 2-chlorophenyl) ethan-1-onez

MS: 527 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.30 (s, 1H), 8.26 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 4.43 (d, J = 13.8 Hz, 1H), 4.31 (d, J = 13.9 Hz, 1H), 4.13 (s, 1H), 3.28- 3.21 (m, 1H), 3.20-3.01 (m, 3H), 2.60 (s, 3H), 1.94-1.74 (m, 4H), 1.45- 1.36 (s, 9H). 21 (S)-1′-(5-((3-chloro- 2-(isopropylamino) pyridin-4-yl)thio) pyrazin-2-yl)-6-(methyl- sulfonyl)-1,3-di- hydrospiro[indene- 2,4′-piperidin]-1- amine

MS: 559 [M + 1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.37 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.81-7.74 (m, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.65 (d, J = 5.7 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.91 (d, J = 5.5 Hz, 1H), 4.28-4.18 (m, 1H), 4.13 (s, 1H), 3.66-3.56 (m, 5H), 3.40- 3.37 (m, 1H), 3.15 (s, 3H), 1.88-1.82 (m, 2H), 1.72-1.67 (m, 2H), 1.27 (d, J = 6.5 Hz, 6H). 22 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyri- dine-6,4′-piperidin]- 7,7-d2-5-amine

MS: 442 [M + 1]⁺. ¹HNMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.35 (d, 1H), 8.29 (s, 1H), 7.70 (d, 1H), 7.67 (d, 1H), 7.20 (dd, 1H), 6.34 (s, 2H), 5.83 (d, 1H), 4.31 (d, 2H), 3.98 (s, 1H), 3.30-3.20 (m, 2H), 3.15 (s, 2H), 1.85-1.67 (m, 2H), 1.57 (d, 1H), 1.22 (d, 1H).

Example 23

To a 0° C. solution of example 1 (132 mg, 0.26 mmol) in THF (8 mL) under nitrogen atmosphere was added LiBH₄ (2M/THF, 0.30 mL, 0.60 mmol). The resulting mixture was stirred for 16 h at 70° C. After cooling to RT, the reaction mixture was quenched with brine (50 mL), extracted with EA (3×40 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:16, v/v) to give example 23 (11 mg). MS: 469 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ7.63 (dd, J=7.9, 1.3 Hz, 1H), 7.50-7.39 (m, 2H), 7.37-7.24 (m, 4H), 4.69 (s, 2H), 4.29 (s, 1H), 3.80-3.58 (m, 2H), 3.26-2.96 (m, 4H), 2.26 (s, 3H), 3.01-1.89 (m, 2H), 1.74-1.59 (m, 2H).

The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

EX No Chemical Name Structure MS & ¹HNMR 24 (S)-(3-(1-amino-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-6-((2- amino-3-chloropyridin-4-yl) thio)-5-methylpyrazin-2- yl)methanol

MS: 483 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 7.62 (d, J = 5.5 Hz, 1H), 7.54- 7.50 (m, 1H), 7.39-7.36 (m, 3H), 5.93 (d, J = 5.5 Hz, 1H), 4.68 (s, 2H), 4.38 (s, 1H), 4.14- 3.85 (m, 4H), 3.21-3.14 (m, 2H), 2.51 (s, 3H), 1.76-1.72 (m, 2H), 1.64-1.57 (m, 2H).

Example 25

To a 0° C. solution of example 2 (0.57 g, 1.29 mmol) in DCM (20 mL) was added NBS (0.35 g, 1.97 mmol). The resulting mixture was stirred for 4 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:30, v/v) to give example 25 (451 mg). MS: 518 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.34 (d, J=4.5 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.65 (dd, J=8.0, 1.5 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.36-7.32 (m, 1H), 7.29-7.25 (m, 1H), 4.09-4.07 (m, 1H), 3.97-3.92 (m, 2H), 3.25-3.16 (m, 3H), 2.95-2.89 (m, 1H), 2.68 (s, 3H), 2.03-1.99 (m, 2H), 1.70-1.65 (m, 1H), 1.51-1.47 (m, 1H).

Example 26 & Example 27

A mixture of example 25 (155 mg, 0.30 mmol), K₄Fe(CN)₆.3H₂O (156 mg, 0.37 mmol), DBU (242 mg, 1.59 mmol) and Pd(PPh₃)₄ (39 mg, 0.034 mmol) in t-BuOH/H₂O (6 mL/6 mL) was stirred for 3.5 h at 100° C. under nitrogen atmosphere. After cooling to RT, the resulting mixture was quenched with brine (50 mL) and extracted with EA (2×30 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 26 (19 mg) and example 27 (25 mg).

Example 26: MS: 465 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.39 (d, J=4.7 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.66 (dd, J=8.0, 1.4 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.35 (dd, J=7.6, 1.4 Hz, 1H), 7.32-7.28 (m, 1H), 4.55-4.49 (m, 2H), 4.18 (s, 1H), 3.52-3.43 (m, 2H), 3.26-3.24 (m, 1H), 3.04-2.99 (m, 1H), 2.29 (s, 3H), 2.03-1.91 (m, 2H), 1.76-1.66 (m, 1H), 1.60-1.54 (m, 1H).

Example 27: MS: 483 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.42 (d, J=4.5 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.62 (dd, J=7.3, 2.3 Hz, 1H), 7.47-7.37 (m, 2H), 7.32 (dd, J=7.5, 5.2 Hz, 1H), 4.24 (s, 1H), 4.13-3.97 (m, 2H), 3.39-3.33 (m, 1H), 3.29-3.20 (m, 2H), 3.09-2.99 (m, 1H), 2.26 (s, 3H), 2.02-1.87 (m, 2H), 1.66-1.50 (m, 2H).

Example 28

A mixture of example 25 (64 mg, 0.12 mmol) and HCl/EA (4 M, 4 mL) was stirred for 1 h at RT. The reaction mixture was filtered followed by EA wash. The solid was dissolved in EA (20 mL) and washed with NH₃H₂O (10%, 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure and dried under high vacuum for 2 h to give example 28 (17 mg) as a yellow solid. MS: 456 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.37 (d, J=4.7 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.67 (dd, J=8.0, 1.4 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.38-7.34 (m, 1H), 7.32-7.28 (m, 1H), 4.11 (s, 1H), 4.04-3.99 (m, 2H), 3.28-3.21 (m, 3H),2.98-2.93 (m, 1H) , 2.27 (s, 3H), 2.10-1.98 (m, 2H), 1.73-1.67(d, J=11.9 Hz, 2H).

Example 29 & Example 30 & Example 31

A mixture of 1,2-dichloro-3-iodobenzene (575 mg, 3.13 mmol), sodium 3-amino-5-chloropyrazine-2-thiolate (813 mg, 2.98 mmol), Pd₂(dba)₃ (134 mg, 0.15 mmol), XantPhos (176 mg, 0.30 mmol) and DIPEA (1.41 g, 10.92 mmol) in 1,4-dioxane (20 mL) was stirred for 3 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give compound 29-1 (0.41 g). MS: 306 [M+1]⁺.

To a 0° C. solution of compound 29-1 (0.40 g, 1.31 mmol) in DCM (20 mL) was added NBS (0.32 g, 1.80 mmol). The resulting mixture was stirred for 17 h at RT. The reaction mixture was diluted with EA (50 mL) and brine (100 mL). The aqueous layer was separated, extracted with EA (1×50 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 29-2 (0.43 g) as a brown solid.

A mixture of compound 29-2 (0.43 g, 1.11 mmol), intermediate C2 (0.43 g, 1.38 mmol) and K₂CO₃ (1.60 g, 11.58 mmol) in CH₃CN (20 mL) was stirred for 5 h at 100° C. After cooling to RT, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give example 29 (191 mg) an a brown solid. MS: 551 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.35 (d, J=4.6 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.35 (dd, J=8.0, 1.2 Hz, 1H), 7.28 (dd, J=7.5, 5.2 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.77 (dd, J=8.0, 1.2 Hz, 1H), 4.14-3.95 (m, 3H), 3.28-3.12 (m, 3H), 2.91 (d, J=16.5 Hz, 1H), 2.08-1.93 (m, 2H), 1.70-1.59 (m, 1H), 1.50-1.42 (m, 1H).

A mixture of example 29 (173 mg, 0.31 mmol), K₄Fe(CN)₆.3H₂O (168 mg, 0.40 mmol), DBU (240 mg, 1.58 mmol) and Pd(PPh₃)₄ (35 mg, 0.030 mmol) in t-BuOH/H₂O (1/1, 16 mL) was stirred for 16 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:12, v/v) to give example 30 (117 mg) as a yellow solid. MS: 498 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.37 (d, J=4.9 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.42-7.38 (m, 1H), 7.34-7.27 (m, 1H), 7.23-7.11 (m, 1H), 6.89-6.86, 6.68-6.65 (m, 1H), 4.55-4.43 (m, 1H), 4.38-4.26 (m, 1H), 4.15-3.99 (m, 1H), 3.65 (t, J=6.9 Hz, 1H), 3.25-3.12 (m, 2H), 3.02-2.91 (m, 1H), 2.13-1.81 (m, 2H), 1.65-1.59 (m, 1H), 1.50-1.42 (m, 1H).

A mixture of example 30 (105 mg, 0.21 mmol) in sulfuric acid (98%, 5 mL) was stirred for 16 h at 80° C. After cooling to RT, the reaction mixture was poured into water and the pH value was taken to 10 with NH₃H₂O (25%). The resulting mixture was extracted with EA (2×50 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 31 (30 mg). MS: 516 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.36 (d, J=4.6 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.36 (dd, J=8.0, 1.1 Hz, 1H), 7.29 (dd, J=7.5, 5.2 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.81 (dd, J=8.0, 1.1 Hz, 1H), 4.07 (s, 1H), 3.99 (d, J=13.7 Hz, 2H), 3.30-3.17 (m, 3H), 2.93 (d, J=16.5 Hz, 1H), 2.03-1.86 (m, 2H), 1.64-1.55 (m, 1H), 1.46-1.40 (m, 1H).

Example 32

Compound 32-1 was synthesized in the manner of compound 5-1, except compound 1-3 was replaced with 6-chloro-3-iodopyridin-2-amine.

A mixture of compound C2-6 (351 mg, 0.86 mmol) and TFA (1 mL) in DCM (20 mL) was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. Compound 32-1 (200 mg, 0.70 mmol), Pd(OAc)₂ (33 mg, 0.15 mmol), DavePhos (65 mg, 0.17 mmol), t-BuOK (1.21 g, 10.78 mmol) and toluene (30 mL) was added. The resulting mixture was stirred for 18 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with water (100 mL) and extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 32-2 (0.37 g) as a brown solid. MS: 558 [M+1]⁺.

A mixture of compound 32-2 (0.37 g, 0.66 mmol) and HCl/EA (4 M, 3.00 mL, 12.00 mmol) in DCM (20 mL) was stirred for 30 min at RT. The resulting mixture was diluted with water (50 mL) and the pH value was adjusted to 9 with NH₃H₂O (25%). The resulting mixture was extracted with DCM (1×50 mL), the organic layer dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 32 (10 mg). MS: 454 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.43 (dd, J=13.1, 4.3 Hz, 1H), 7.96-7.88 (m, 1H), 7.60 (d, J=5.2 Hz, 1H), 7.43-7.29 (m, 2H), 6.24 (d, J=8.5 Hz, 1H), 6.01 (d, J=5.2 Hz, 1H), 4.42-4.15 (m, 3H), 3.26-3.08 (m, 4H), 1.86-1.77 (m, 2H), 1.59-1.43 (m, 2H).

Example 33

A mixture of compound C2-6 (552 mg, 1.35 mmol) and TFA (2.50 mL) in DCM (30 mL) was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. 2-Bromo-5-iodopyridine (354 mg, 1.25 mmol), Pd₂(dba)₃ (66 mg, 0.072 mmol), BINAP (86 mg, 0.14 mmol), t-BuOK (3204 mg, 28.55 mmol) and toluene (20 mL) was added. The resulting mixture was stirred for 21 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA (50 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give compound 33-1 (392 mg) as a yellow solid. MS: 463 [M+1]⁺.

A mixture of compound 33-1 (184 mg, 0.40 mmol), intermediate Al (80 mg, 0.44 mmol), Pd₂(dba)₃ (41 mg, 0.045 mmol), XantPhos (55 mg, 0.095 mmol) and DIPEA (193 mg, 1.49 mmol) in 1,4-dioxane (20 mL) was stirred for 16 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:12, v/v) to give compound 33-2 (127 mg). MS: 543 [M+1]⁺.

A mixture of compound 33-2 (127 mg, 0.23 mmol) and HCl/EA (4 M, 3.00 mL, 12.00 mmol) in DCM (20 mL) was stirred for 1.5 h at RT. The reaction mixture was diluted with water (50 mL) and the pH value was adjusted to 9 with NH₃H₂O (25%). The resulting mixture was extracted with DCM (2×50 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 33 (28 mg). MS: 439 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.45-8.34 (m, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.67-7.54 (m, 2H), 7.53-7.44 (m, 1H), 7.37-7.25 (m, 1H), 5.95 (d, J=5.5 Hz, 1H), 4.11 (s, 1H), 3.93-3.75 (m, 2H), 3.28-3.10 (m, 3H), 3.01-2.83 (m, 1H), 2.07-1.84 (m, 2H), 1.76-1.66 (m, 1H), 1.57-1.45 (m, 1H).

Example 34

1-Bromo-4-fluorobenzene (3.69 g, 21.09 mmol), intermediate C2 (0.95 g, 3.04 mmol), K₂CO₃ (5.21 g, 37.70 mmol) and NMP (6 mL) was added to a 15 mL sealed tube. The resulting mixture was stirred for 6.5 h at 140° C. An additional batch of 1-bromo-4-fluorobenzene (1.22 g, 6.97 mmol) was added and the resulting mixture was stirred for 18 h at 160° C. After cooling to RT, the reaction mixture was poured into water (50 mL) and extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:15, v/v) to give compound 34-1 (249 mg) as a brown oil. MS: 358 [M+1]⁺.

A mixture of compound 34-1 (120 mg, 0.33 mmol), intermediate Al (65 mg, 0.36 mmol), Pd₂(dba)₃ (61 mg, 0.067 mmol), XantPhos (83 mg, 0.14 mmol) and DIPEA (303 mg, 2.34 mmol) in 1,4-dioxane (10 mL) was stirred for 18 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give example 34 (47 mg). MS: 438 [M+1]⁺.¹HNMR (400 MHz, methanol-d₄) δ8.47 (d, J=4.6 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.56 (d, J=5.5 Hz, 1H), 7.43 (d, J=8.7 Hz, 2H), 7.39-7.33 (m, 1H), 7.13 (d, J=8.7 Hz, 2H), 5.88 (d, J=5.5 Hz, 1H), 4.31 (s, 1H), 3.87-3.74 (m, 2H), 3.27-3.02 (m, 4H), 2.02-1.91 (m, 2H), 1.73-1.60 (m, 2H).

The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

EX No Chemical Name Structure MS & ¹HNMR 35 (S)-1′-(4-((2-amino- 3-chloropyridin-4- yl)thio)isoquinolin-1- yl)-1,3-dihydrospiro [indene- 2,4′-piperidin]-1-amine

MS: 488 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 8.38 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.47-7.32 (m, 5H), 5.63 (d, J = 5.6 Hz, 1H), 4.48 (s, 1H), 4.06-3.87 (m, 2H), 3.52-3.37 (m, 2H), 3.21 (d, J = 7.5 Hz, 1H), 2.25-2.06 (m, 2H), 1.89-1.83 (m, 1H), 1.79-1.72 (m, 1H).

Example 36

To a solution of 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (10.00 g, 62.28 mmol) in EtOH (200 mL) was added hydrazine hydrate (80%, 52.00 mL) at RT. The resulting mixture was stirred for 4 h at 80° C. After cooling to RT, the reaction mixture was concentrated to about 100 mL under reduced pressure and filtered. The filtered cake was washed with EtOH (2×50 mL). The filtered cake was collected and dried in a high vacuum oven to give compound 36-1 (5.56 g) as a light yellow solid. MS: 157 [M+1]⁺.

A mixture of compound 36-1 (5.56 g, 35.61 mmol) and 4-methoxybenzaldehyde (7.02 g, 51.56 mmol) in MeOH was stirred for 6 h at 70° C. After cooling to RT, the reaction mixture was filtered and the filtered cake was washed with MeOH. The filtered cake was collected and dried under high vacuum to give compound 36-2 (5.78 g) as a yellow solid. MS: 275 [M+1]⁺.

A mixture of compound 36-2 (2.03 g, 7.40 mmol), 2,3-dichlorobenzaldehyde (1.36 g, 7.77 mmol) and piperidine (0.77 g, 9.04 mmol) in DMF/iPrOH (20 mL/10 mL) was stirred for 18 h at 85° C. After cooling to RT, the reaction mixture was diluted with EA (200 mL) and washed with brine (2×50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound 36-3 (2.40 g) as a light yellow solid. MS: 431 [M+1]⁺.

A mixture of compound 36-3 (197 mg, 0.46 mmol) and BOP (649 mg, 1.47 mmol) in DMF (17 mL) was stirred for 10 min at RT. Then DBU (748 mg, 4.91 mmol) and C2 (229 mg, 0.73 mmol) was added and stirred for 20 h at RT. The reaction mixture was diluted with EA (100 mL) wad washed with brine (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:8, v/v) to give compound 36-4 (210 mg). MS: 615 [M+1]⁺.

A mixture of compound 36-4 (210 mg, 0.34 mmol) and TFA (15 mL) was stirred for 1.5 h at 100° C. The reaction mixture was diluted with water (100 mL) and the pH value was taken to 10 with NH₃H₂O (25%). The resulting mixture was extracted with DCM (2×50 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 36 (21 mg). MS: 496 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.38 (d, J=4.7 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.65 (dd, J=7.9, 1.5 Hz, 1H), 7.46 (dd, J=7.6, 1.5 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.31 (dd, J=7.4, 5.2 Hz, 1H), 4.14 (s, 1H), 3.68-3.58 (m, 2H), 3.55 (s, 3H), 3.29-3.12 (m, 3H), 3.01-2.90 (m, 1H), 2.15-1.96 (m, 2H), 1.74-1.65 (m, 1H), 1.57-1.45 (m, 1H).

The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

EX No Chemical Name Structure MS & ¹HNMR 37 (S)-6-(1-amino-6-fluoro- 1,3-dihydrospiro[indene- 2,4′-piperidin]- 1′-yl)-3-(2,3-dichloro phenyl)-5-methyl-1,5- dihydro-4H- pyrazolo[3,4- d]pyrimidin-4-one

MS: 513 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 7.65 (dd, J = 7.9, 1.7 Hz, 1H), 7.45 (dd, J = 7.6, 1.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.26 (dd, J = 8.2, 5.1 Hz, 1H), 7.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.03-6.93 (m, 1H), 4.10 (s, 1H), 3.63-3.55 (m, 2H), 3.54 (s, 3H), 3.25-3.09 (m, 3H), 2.88-2.79 (m, 1H), 2.10-1.95 (m, 2H), 1.72- 1.65 (m, 1H), 1.57-1.49 (m, 1H). 38 (S)-6-(1-amino-5,6,7- trifluoro-1,3- dihydrospiro[indene- 2,4′-piperidin]-1′-yl)-5- methyl-3-(5- methylthiophen- 2-yl)-1,5-dihydro-4H- pyrazolo[3,4-d] pyrimidin-4-one

MS: 501 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 8.22 (d, J = 3.6 Hz, 1H), 7.10-6.99 (m, 1H), 6.81 (d, J = 3.5 Hz, 1H), 4.28 (s, 1H), 3.59 (s, 3H), 3.57-3.43 (m, 2H), 3.26-3.15 (m, 4H), 2.54 (s, 3H), 1.92-1.76 (m, 4H).

Example 39

A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.53 g, 13.46 mmol), (4-methoxyphenyl)methanol (2.00 mL) and t-BuOK/THF (1 M, 53.00 mL, 53.00 mmol) in 1,4-dioxane (20 mL) was stirred for 2 h at RT. The reaction mixture was quenched with sat.aq.NH₄Cl and extracted with EA (2×100 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 39-1 (4.22 g) as a light yellow solid which was used in next step without further purification. MS: 290 [M+1]⁺.

A mixture of compound 39-1 (4.22 g, 14.57 mmol) and NBS (2.96 g, 16.63 mmol) in DMF (35 mL) was stirred for 20 min at RT. The reaction mixture was diluted with sat.aq.Na₂SO₃ (200 mL), extracted with EA (2×100 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 39-2 (4.76 g) as a brown solid which was used in next step without further purification. MS: 368 [M+1]⁺.

A mixture of compound 39-2 (4.76 g, 12.91 mmol), (Boc)₂O (2.97 g, 13.61 mmol), DIPEA (5.05 g, 39.07 mmol) in DMF (40 mL) was stirred for 16 h at RT. To the mixture was added DMAP (52 mg, 0.43 mmol) and stirred for another 1 h at 40° C. The reaction mixture purified by silica gel chromatography (eluting with EA:Hex=1:30, v/v) to give compound 39-3 (2.82 g) as a white solid. MS: 468 [M+1]⁺.

A mixture of compound 39-3 (500 mg, 1.07 mmol), (2,3-dichlorophenyl)boronic acid (215 mg, 1.13 mmol), K₂CO₃ (606 mg, 4.38 mmol) and Pd(dppf)C₂ (102 mg, 0.14 mmol) in THF/H₂O (5.0 mL/0.5 mL) was stirred for 3 h at 90° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with brine (50 mL), extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give compound 39-4 (380 mg). MS: 534 [M+1]⁺.

A mixture of compound 39-4 (241 mg, 0.56 mmol), C2 (210 mg, 0.67 mmol) and K₂CO₃ (1903 mg, 13.77 mmol) in NMP (15 mL) was stirred for 23 h at 140° C. After cooling to RT, the reaction mixture was diluted with EA (100 mL) and washed with brine (3×50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:10, v/v) to give compound 39-5 (39 mg) as a brown solid. MS: 601 [M+1]⁺.

A mixture of compound 39-5 (38 mg, 0.063 mmol) and TFA (2 mL) in DCM (10 mL) was stirred for 1 h at RT. The reaction mixture was diluted with brine (50 mL) and the pH value was taken to 10 with NH₃H₂O (25%). The resulting mixture was extracted with DCM (2×30 mL), the organic layers combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:6, v/v) to give example 39 (12 mg). MS: 481 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.43 (d, J=4.7 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.42 (dd, J=7.8, 1.5 Hz, 2H), 7.33 (dd, J=7.5, 5.2 Hz, 1H), 7.28-7.21 (m, 1H), 6.87 (s, 1H), 4.28-4.18 (m, 2H), 4.16 (s, 1H), 3.31-3.20 (m, 3H), 3.05-2.94 (m, 1H), 1.98-1.82 (m, 2H), 1.65-1.58 (m, 1H), 1.51-1.45 (m, 1H).

Example 40

A mixture of 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (0.50 g, 3.54 mmol) and PyBOP (5.62 g, 10.80 mmol) in DMF (15 mL) was stirred for 10 min at RT. Then DBU (5.62 g, 36.92 mmol) and Cl (1.39 g, 5.05 mmol) was added and stirred for 3 h at RT. The reaction mixture was diluted with EA (100 mL) wad washed with brine (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:5, v/v) to give compound 40-1 (1135 mg) as a yellow oil. MS: 326 [M+1]⁺.

A mixture of compound 40-1 (1.13 g, 3.47 mmol) and NIS (859 mg, 3.82 mmol) in DMF (10 mL) was stirred for 17 h at RT. The reaction mixture was diluted with EA (200 mL) and washed sat.aq.Na₂SO₃ with EA (2×80 mL) and sat.aq.NH₄Cl (1×80 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:8, v/v) to give compound 40-2 (828 mg). MS: 452 [M+1]⁺.

A mixture of compound 40-2 (103 mg, 0.23 mmol), intermediate Al (48 mg, 0.26 mmol), Pd₂(dba)₃ (21 mg, 0.023 mmol), XantPhos (25 mg, 0.043 mmol) and DIPEA (103 mg, 0.80 mmol) in 1,4-dioxane (10 mL) was stirred for 15 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was filtered through Kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by Prep—TLC (eluting with MeOH:DCM=1:10, v/v) to give example 40 (12 mg). MS: 484 [M+1]⁺.¹HNMR (400 MHz, methanol-d₄) δ7.62 (d, J=5.5 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.45-7.32 (m, 3H), 6.19 (d, J=5.5 Hz, 1H), 4.42 (s, 1H), 3.80-3.63 (m, 2H), 3.47 (s, 3H), 3.30-3.09 (m, 4H), 2.11-1.89 (m, 2H), 1.75 (d, J=12.9 Hz, 1H), 1.66 (d, J=13.2 Hz, 1H).

Example 41

A mixture of 2,4-dichlorothiazole (1.54 g, 10.00 mmol), sodium 3-amino-5-chloropyrazine-2-thiolate -(2.77 g, 15.10 mmol) and K₂CO₃ (2.92 g, 21.10 mmol) in DMF (15 mL) was stirred for 3 h at 75° C. After cooling to RT, the reaction mixture was diluted with EA (50 mL) and water (50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:5, v/v) to give compound 41-1 (281 mg) as a yellow solid. MS: 279 [M+1]⁺.

To a solution of intermediate C3 (288 mg, 0.70 mmol) in DCM (17 mL) was added TFA (2 mL), and stirred for 1.5 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in NMP (5 mL), 41-1 (232 mg, 1.19 mmol) and K₂CO₃ (1.18 g, 8.52 mmol) was added. The resulting mixture was stirred for 16 h at 95° C. After cooling to RT, the reaction mixture was diluted with water (30 mL) and EA (30 mL). The aqueous layer was separated and extracted with EA (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 41-2 (272 mg) as a red oil. MS: 556 [M+1-1]⁺.

A mixture of compound 41-2 (254 mg, 0.43 mmol) and HC1/1, 4-dioxane (4M, 1 mL) in DCM was stirred for 30 min at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give 41 (34 mg) as a yellow solid. MS: 452 [M+1-1]⁺.¹HNMR (400 MHz, methanol-d₄) δ9.01 (s, 1H), 7.63 (s, 1H), 7.26 (s, 1H), 4.50-4.28 (m, 3H), 3.46-3.35 (m, 1H), 3.31-3.21 (m, 2H), 3.19-3.09 (m, 1H), 2.00-1.76 (m, 4H).

Example 42

A mixture of compound B2-1 (192 mg, 1.34 mmol), (S)-1-amino-1,3-dihydrospiro [indene-2,4′-piperidine]-6-carbonitrile dihydrochloride (406 mg, 1.35 mmol), K₂CO₃ (2132 mg, 15.43 mmol) and NMP (8 mL) was stirred for 1.5 h at 140° C. After cooling to RT, the reaction mixture was diluted with water (20 mL) and extracted with EA (2 A 50 mL). The combined organic layers were washed with brine (1 b 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:10, v/v) to give compound 42-1 (202 mg) as a brown oil. MS: 335 [M+1]⁺.

A mixture of compound 42-1 (202 mg, 0.60 mmol), NIS (167 mg, 0.74 mmol) and THF (8 mL) was stirred for 19 h at RT. The reaction mixture was diluted with brine (50 mL) and extracted with EA (2 2 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:20, v/v) to give compound 42-2 (79 mg) as a yellow solid. MS: 461 [M+1]⁺.

A mixture of compound 42-2 (79 mg, 0.17 mmol), sodium 4-amino-5-bromopyrimidine-2-thiol (57 mg, 0.25 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), XantPhos (21 mg, 0.036 mmol) and DIPEA (75 mg, 0.58 mmol) in 1,4-dioxane (8 mL) was stirred for 2 h at 90° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:10, v/v) to give example 42 (15 mg) as a yellow solid. MS: 538 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.02 (s, 1H), 7.93 7.76 (m, 2H), 7.70 7.64 (m, 1H), 7.50 (d, J=7.5 Hz, 1H), 6.18 (d, J=8.0 Hz, 1H), 4.29 (s, 1H), 3.62 (s, 3H), 3.46 3.36 (m, 2H), 3.30 3.15 (m, 4H), 2.06 1.90 (m, 2H), 1.77 1.67 (m, 2H).

The following compound was synthesized in the similar manner of example 42.

EX No Chemical Name Structure MS & ¹HNMR 43 (S)-6-(1-amino-6- bromo-1,3-dihydrospiro [indene-2,4′-piperidin]-1′- yl)-3-((3-chloro-2- methoxypyridin- 4-yl)thio)-1- methylpyridin-

MS: 561 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 7.93 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 5.5 Hz, 1H), 7.69 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.35 (d, J = 5.5 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 4.39 (s, 1H), 3.98 2(1H)-one (s, 3H), 3.62 (s, 3H), 3.21-2.90 (m, 6H), 2.10-1.95 (m, 2H), 1.79- 1.64 (m, 2H).

Example 44

Solution of 2,4-dibromothiazole (202 mg, 0.83 mmol), (S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile dihydrochloride (382 mg, 1.27 mmol) and TEA (1609 mg, 15.90 mmol) in DMF (8 mL) was stirred for 30 h at 90° C. The reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 44-1 (243 mg) as a light yellow solid. MS: 389 [M+1]⁺.

A mixture of intermediate A2 (420 mg, 1.67 mmol), compound 44-1 (135 mg, 0.53 mmol), Pd(PPh₃)₄ (127 mg, 0.11 mmol), Na₂CO₃ (1120 mg, 10.57 mmol), THF (20 mL) and H₂O (2 mL) was stirred for 16 h at 90° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with brine (100 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:50, v/v) to give the crude product and was further purified by Prep—TLC (MeOH:DCM=1:40, v/v) to give example 44 (20 mg) as an off-white solid. MS: 515 [M+1]⁺.¹HNMR (400 MHz, methanol-d₄) δ8.36 (s, 1H), 7.91 7.79 (m, 4H), 7.72 7.68 (m, 1H), 7.60 7.45 (m, 3H), 7.21 7.13 (m, 1H), 4.31 (s, 1H), 4.20 3.94 (m, 3H), 3.47 3.36 (m, 2H), 3.08 (m, 1H), 1.94 1.81 (m, 2H), 1.75 1.63 (m, 2H).

Example 45

A mixture of 1-bromo-2-chloro-3-methylbenzene (2.89 g, 14.06 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.43 g, 21.38 mmol), Pd(dppf)C₂CH₂C₂ (1.21 g, 1.65 mmol), Na₂CO₃ (5.56 g, 52.46 mmol) in 1,4-dioxane (30 mL) was stirred for 22 hat 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:4, v/v) to give the compound 45-1 (2.17 g).

A mixture of compound 45-1 (1.00 g, 3.96 mmol), 3-bromo-6-chloropyrazin-2-amine (1.03 g, 4.94 mmol), Pd(dppf)C₂CH₂Cl₂ (0.84 g, 1.15 mmol), K₂CO₃ (2.37 g, 17.15 mmol), CH₃CN (40 mL) and H₂O (4 mL) was stirred for 2 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA and filtered through a pad of Celite. The filtrate was washed with brine, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:15, v/v) to give the compound 45-2 (2.17 g). MS: 254 [M+1]⁺.

A mixture of compound 45-2 (102 mg, 0.40 mmol), (S)-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine dihydrochloride (205 mg, 0.42 mmol), K₂CO₃ (1562 mg, 11.30 mmol) and CH₃CN (20 mL) was stirred for 16 h at 100° C. After cooling to RT, the reaction mixture was diluted with EA (50 mL) filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:12, v/v) to give example 45 (89 mg) as a yellow solid. MS: 498 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ7.61 (s, 1H), 7.49-7.43 (m, 2H), 7.38 (d, J=7.0 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.23 (dd, J=10.8, 7.9 Hz, 2H), 4.24 (t, J=13.6 Hz, 2H), 4.17 (s, 1H), 3.25-3.10 (m, 3H), 2.92 (d, J=16.2 Hz, 1H), 2.46 (s, 3H), 1.92-1.74 (m, 2H), 1.65-1.47 (m, 2H).

The following examples were synthesized in the similar manner of example 45.

EX No Chemical Name Structure MS & ¹HNMR 46 (S)-1′-(5-(3-amino-2- (trifluoromethyl)phenyl) pyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′- piperidine]-1,6-diamine

MS: 455 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 8.63 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H) 7.12 (d, J = 8.0 Hz, 2H), 6.89-6.72 (m, 3H), 4.68-4.53 (m, 2H), 4.23 (s, 1H), 3.44-3.37 (m, 2H), 3.09-3.03 (m, 2H), 1.76-1.61 (m, 4H). 47 (S)-1′-(6-amino-5-(2- chloro-3-methylphenyl) pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′- piperidine]-1,6-diamine

MS: 435 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 7.46 (s, 1H), 7.38 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.24-7.18 (m, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.74 (dd, J = 8.0, 2.0 Hz, 1H), 4.35- 4.07 (m, 3H), 3.28-3.09 (m, 2H), 3.07-2.90 (m, 2H), 2.45 (s, 3H), 1.88- 1.73 (m, 2H), 1.70-1.56 (m, 2H). 48 (S)-1′-(6-(5- chlorothiophen- 2-yl)pyridazin-3-yl)-5- methyl-1,3-dihydrospiro [indene-2,4′- piperidin]-1-amine

MS: 411 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 7.83 (d, J = 9.7 Hz, 1H), 7.42-7.31 (m, 3H), 7.21 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 4.45-4.36 (m, 1H), 4.33 (s, 1H), 4.26-4.15 (m, 1H), 3.45- 3.34 (m, 2H), 3.17 (s, 2H), 2.38 (s, 3H), 1.95-1.84 (m, 1H), 1.83-1.70 (m, 2H), 1.68-1.56 (m, 1H). 49 (S)-1′-(6′-chloro-[3,3′- bipyridazin]-6-yl)-5- methyl-1,3-dihydrospiro [indene-2,4′- piperidin]-1-amine

MS: 407 [M + 1]⁺. ¹HNMR (400 MHz, methanol - d₄) δ 8.63 (d, J = 9.1 Hz, 1H), 8.43 (d, J = 9.7 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.46 (d, J = 9.7 Hz, 1H), 7.19 (s, 1H), 7.18-7.11 (m, 2H), 4.50 (d, J = 13.8 Hz, 1H), 4.40-4.35 (m, 1H), 4.28-4.25 (m, 1H), 3.48- 3.43 (m, 2H), 3.18-3.11 (m, 2H), 2.37 (s, 3H), 1.94-1.78 (m, 4H).

Example 50

A solution of compound C1-4 (1.90 g, 4.67 mmol) and TFA (6.00 mL) in DCM (20 mL) was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. 3,5-Dichloropyrazine-2-carbonitrile (818 mg, 4.70 mmol), DMSO (8 mL) and DIPEA (6.56 g, 50.76 mmol) was added and stirred for 1 h at 70° C. The reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound 50-1 (1.81 g). MS: 444 [M+1]⁺.

A mixture of compound 50-1 (1.81 g, 4.08 mmol), (4-methoxybenzyl)hydrazine hydrochloride (0.94 g, 4.98 mmol), TEA (4.60 g, 45.46 mmol) and EtOH (20 mL) was stirred for 18 h at 90° C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EA (100 mL), washed with sat.aq.NH₄Cl (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under high vacuum to give compound 50-2 (2.19 g) as a yellow solid. MS: 560 [M+1]⁺.

A solution of compound 50-2 (1.58 g, 2.82 mmol), tert-butyl nitrite (0.36 g, 3.49 mmol) and CH₂I₂ (1.60 g, 5.97 mmol) in CH₃CN (30 mL) was stirred for 1.5 h at 90° C. The reaction mixture was diluted with brine (150 mL), MeOH (20 mL) and extracted with EA (2×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. To the obtained red solid was added EA (20 mL), filtered and the filter cake was collected. The crude 50-3 (1.02 g) was used in next step without further purification. MS: 567 [M+1]⁺.

A mixture of compound 50-3 (236 mg, 0.42 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (62 mg, 0.46 mmol), Pd2(dba)3 (77 mg, 0.084 mmol), BINAP (59 mg, 0.094 mmol) and t-BuONa (121 mg, 1.26 mmol) in toluene (10 mL) was stirred for 16 h at 90° C. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give the crude product and was further purified by Prep TLC (MeOH:DCM=1:20, v/v) to give compound 50-4 (45 mg) as a yellow solid. MS: 573 [M+1]⁺.

A mixture of compound 50-4 (34 mg, 0.059 mmol), TFA (3.0 mL), H₂SO₄ (98%, 0.2 mL) and anisole (0.5 mL) was stirred for 4 h at 90° C. The pH value of the reaction mixture was adjusted to 9 with sat.aq.Na₂CO₃. The resulting mixture was extracted with EA (2×20 mL), the organic layers combined, dried over anhydrous Na₂SO₄ and concentrated reduced pressure. The residue was purified by Prep TLC (MeOH:DCM=1:10, v/v) to give example 50 (3 mg) as a light yellow solid. MS: 453 [M+1]⁺.

Example 51

A mixture of 1-bromo-3-chloro-5-methoxybenzene (2.05 g, 9.26 mmol), 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (733 mg, 2.27 mmol) and DMF (15 mL) was stirred for 18 h at 50° C. The reaction mixture was quenched with water (15 mL) and extracted with EA (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 51-1 (2.60 g) as a white solid.

A mixture of 5-bromo-2-chloropyridine (100 mg, 0.52 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (145 mg, 0.57 mmol), Pd(dppf)C₂ (19 mg, 0.026 mmol) and CH₃COOK (153 mg, 1.56 mmol) in 1,4-dioxane (10 mL) was stirred for 2.5 h at 90° C. under nitrogen atmosphere. To the resulting mixture was added compound 51-1 (148 mg, 0.58 mmol), Pd(dppf)C₂ (21 mg, 0.029 mmol), CH₃COOK (154 mg, 1.57 mmol). The resulting mixture was stirred for 16 h at 70° C. After cooling to RT, the reaction mixture was diluted with water (20 mL) and extracted with EA (2×15 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give the compound 51-2 (28 mg). MS: 288 [M+1]⁺.

Example 51 was synthesized in the similar manner of example 1, except compound 1-4 was replaced with compound 51-2. MS: 454 [M+1]⁺.¹HNMR (400 MHz, methanol-d₄) δ8.16 (d, J=2.3 Hz, 1H), 7.68 (dd, J=8.9, 2.5 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.43-7.29 (m, 3H), 7.14 (d, J=2.9 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 6.89 (d, J=2.9 Hz, 1H), 4.59 (s, 1H), 4.47-4.33 (m, 2H), 3.86 (s, J=7.9 Hz, 3H), 3.26-3.06 (m, 3H), 3.00-2.89 (m, 1H), 1.93-1.72 (m, 4H).

Example 52 & Example 53

Example 52 was prepared following procedures of example 51 from intermediate B2. MS: 442 [M+1]⁺.¹HNMR (400 MHz, methanol-d₄) δ8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.04 (dd, J=8.1, 1.5 Hz, 1H), 7.79-7.66 (m, 2H), 7.28 (t, J=7.9 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.28 (d, J=7.9 Hz, 1H), 4.20 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.58 (t, J=6.0 Hz, 1H), 3.28-3.22 (m, 1H), 3.13-2.99 (m, 3H), 2.93-2.84 (m, 1H), 2.10-1.96 (m, 2H), 1.75-1.64 (m, 2H).

A solution of example 52 (10 mg, 0.023 mmol), KOH (40 mg, 0.71 mmol) in MeOH (2 mL) and H₂O (2 mL) was stirred for 4 h at 100° C. The reaction mixture was diluted with water (5 mL), extracted with EA (2×5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the example 53 (7 mg) as a yellow solid. MS: 460 [M+1]⁺. ¹HNMR (400 MHz, methanol-d₄) δ8.57 (d, J=4.7 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.75-7.68 (m, 1H), 7.66-7.54 (m, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.33-7.26 (m, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.19 (d, J=7.7 Hz, 1H), 4.27 (s, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 3.27-3.17 (m, 2H), 3.07-2.93 (m, 4H), 1.81-1.63 (m, 4H).

Example 54

To a −80° C. solution of 1-bromo-3-chloro-5-methoxybenzene (2.24 g, 10.11 mmol) in THF (50 mL) under nitrogen atmosphere was added n-BuLi (2.5 M, 7.40 mL, 18.50 mmol) dropwise. The resulting mixture was stirred for 40 min at −80° C. Then 1,4-dioxaspiro[4.5]decan-8-one (dissolved in 9 mL THF, 1.62 g, 10.37 mmol) was added dropwise and the resulting mixture was stirred for 40 min. The reaction mixture was quenched with brine (10 mL), diluted with water (100 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 54-1 (3.73 g) as a yellow oil.

A suspension of compound 54-1 (3.72 g, 13.25 mmol), Pd/C (Pd 10%, H₂O 54.55%, 6.07 g) in MeOH (50 mL) was stirred for 2 h at RT under hydrogen atmosphere. The reaction mixture was filtered through a Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in acetone (60 mL) and HCl (aq, 2M, 20 mL) was added. The resulting mixture was stirred for 1 h at 60° C. The reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 54-2 (1.82 g) as a white solid. ¹H NMR (400 MHz, d-DMSO) 6 7.17 (t, J=8.1 Hz, 1H), 6.86-6.79 (m, 2H), 6.76-6.69 (m, 1H), 3.70 (s, 3H), 3.04-2.89 (m, 1H), 2.57-2.44 (m, 2H), 2.29-2.19 (m, 2H), 2.06-1.97 (m, 2H), 1.89-1.74 (m, 2H).

A solution of intermediate C2-6 (115 mg, 0.28 mmol), TFA (2 mL) and DCM (10 mL) was stirred for 1 h at RT. To the resulting mixture was added compound 54-2 (57 mg, 0.28 mmol), TsOH (5 mg) and NaBH(OAc)₃ (120 mg, 0.57 mmol). The resulting mixture was stirred for 3 days at RT. The reaction mixture was diluted with brine (30 mL) and extracted with DCM (2×30 mL), the organic layers combined, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:15, v/v) to give compound 54-3 (30 mg) as a white solid. MS: 496 [M+1]⁺.

A mixture of compound 54-3 (30 mg, 0.061 mmol) and HCl/EA (4 M, 1.00 mL, 4.00 mmol) in EA (10 mL) was stirred for 2.0 h at RT. The reaction mixture was diluted with water (20 mL) and the pH value was taken to 9 with NH₃H₂O (25%). The resulting mixture was extracted with EA (2×20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give example 54 (8 mg) as a brown solid. MS: 392 [M+1]⁺.

The following compounds were synthesized using the above procedure or modified procedure with the corresponding starting materials.

MS: EX Chemical Name Structure [M + 1]⁺ 55 (S)-1-amino-1′-(6-((3-amino-2-chloro phenyl)thio)-1,2,4-triazin-3-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-6- carbonitrile

464 56 1-(5-((5-((1S)-1-amino-6-(methylsulfinyl)- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)pyrazin-2-yl)thio)-2- chlorophenyl)ethan-1-one

527 57 (S)-1′-(5-(pyrimidin-2-ylthio) pyrazin-2-yl)-6-(trifluoromethyl)- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1-amine

459 58 (S)-6-bromo-5-fluoro-1′-(5-(quinolin- 4-ylthio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine

536 59 (S)-6-(4-amino-4,6-dihydrospiro [cyclopenta[b]thiophene-5,4′-piperidin]- 1′-yl)-3-(3-(trifluoromethyl)pyridin- 4-yl)-1,5-dihydro-4H-pyrazol[3,4- d]pyrimidin-4-one

488 60 (S)-2-(1-amino-6-chloro-5-methoxy- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-5-(3,5- dichloropyridin-4-yl)-3-methyl- 3,7-dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one

559 61 (S)-1′-(7-(5-chloropyridin-2-yl)-5H- pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta] naphthalene-2,4′-piperidin]- 3-amine

481 62 (S)-1′-(7-(3-chloropyridin-2-yl)-5H- pyrrolo[2,3-b]pyrazin-3-yl)-1H,3H- spiro[phenalene-2,4′-piperidin]- 1-amine

481 63 (R)-1′-(3-(2-methylpyridin-3-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-3,4- dihydro-1H-spiro[naphthalene-2,4′- piperidin]-3-amine

426 64 (S)-6-amino-2-(1-amino-7-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-3-methyl-5-phenylpyrimidin- 4(3H)-one

480 65 (S)-1-amino-1′-(4-amino-6-oxo-5- (pyridazin-3-ylthio)-1,6- dihydropyrimidin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-7-carbonitrile

447 66 (S)-1-amino-1′-(1-methyl-6-oxo-5- (pyrazin-2-yl)-1,6-dihydropyrimidin- 2-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-7-carbonitrile

414 67 (S)-2-(1-amino-6-chloro-5-methoxy- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-5-((4- isopropylphenyl)thio) pyrimidin-4(3H)-one

511 68 (S)-4-amino-6-(1-amino-6-bromo-5- fluoro-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-3-(2-chloro- 3-methylphenyl)-1-methylpyridin- 2(1H)-one

545 69 (S)-6-(4-acetyl-1-amino-1,3-dihydrospiro [indene-2,4′-piperidin]-1′- yl)-4-amino-3-(4-(trifluoromethyl) phenyl)pyridin-2(1H)-one

497 70 (S)-6′-(1-amino-4-hydroxy-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-2′-oxo- 1′,2′-dihydro-[3,3′- bipyridine]-2-carbonitrile

414 71 (S)-1′-(3-bromo-5-(1H-indol-6-yl)-6- methylpyrazin-2-yl)-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-4-amine

495 72 (S)-3-(4-amino-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-1′-yl)-5-methyl-6- (2-oxoindolin-7-yl)pyrazine-2- carbonitrile

458 73 (S)-1′-(5-amino-6-((2-amino-3-chloro pyridin-4-yl)thio)-1,2,4-triazin-3-yl)- 5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-5-amine

456 74 (S)-1′-(5-amino-6-((2-amino-3-chloro pyridin-4-yl)thio)pyridin-3-yl)-6- chloro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine

487 75 (S)-1′-(4-amino-5-((2-amino-3-chloro pyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopena[b] pyridine-6,4′-piperidin]-5-amine

454 76 (S)-1′-(5-((2,3-dichlorophenyl)thio) thiazol-2-yl)-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′- piperidin]-7-amine

463 77 (R)-1′-(4-((3-chloropyridin-4-yl)thio) thiazol-2-yl)spiro[indoline-2,4′- piperidin]-3-amine

430 78 (R)-1′-(2-(7-chloro-1H-indol-1-yl) thiazol-4-yl)-2,3-dihydrospiro [indene-1,4′-piperidin]- 2-amine

435 79 (R)-1′-(2-((2-(trifluoromethyl) phenyl)thio)thiazol-5-yl)-3H- spiro[benzofuran-2,4′- piperidin]-3-amine

464 80 (S)-(5-(1-amino-1,3-dihydrospiro [indene-2,4′-piperidin]-1′- yl)pyrazin-2-yl)(2,3- dichlorophenyl)methanone

453 81 (S)-2-(1-amino-6-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-(indolin-1-yl)-3- methyl-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one

485 82 (S)-1′-(5-((1,2,3,4-tetrahydroquinolin- 8-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[b] naphthalene-2,4′- piperidin]-1-amine

494 83 (S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[a] naphthalene-2,4′-piperidin]-1- amine

489 84 1′-(5-((3-amino-2-chlorophenyl)thio)- 6-methylpyrazin-2-yl)-1-methyl-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine

466 85 (R)-1′-(7-((2-amino-3-chloropyridin- 4-yl)thio)-1H-indol-4-yl)-3H-spiro [benzofuran-2,4′-piperidin]-3- amine

478 86 (S)-1′-(7-((2-amino-3-chloropyridin- 4-yl)thio)isoquinolin-3-yl)-5,6- dibromo-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine

644 87 (S)-4-((5-(5-acetyl-1-amino-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-3- aminopyrazin-2-yl)thio)-3-chloro- 1-methylpyridin-2(1H)-one

511 88 (S)-5-(1-amino-6-bromo-1,3-dihydro spiro[indene-2,4′- piperidin]-1′-yl)-2-(2,3- dichlorophenyl)thio)-6-(hydroxy methyl)pyridin-3-ol

480 89 (S)-6-bromo-1′-(5-(2,3-dichlorophenyl)- 6-methylimidazo[1,5-a]pyrazin-8- yl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine

556 90 (S)-1′-(7-((2-amino-3-chloropyridin- 4-yl)thio)-[1,2,5]thiadiazolo[3,4-c] pyridin-4-yl)-6-bromo-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine

574 91 (S)-1′-(8-((2-amino-3-chloropyridin- 4-yl)thio)pyrido[4,3-d]pyrimidin-5-yl)- 6-bromo-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine

568 92 (S)-3-(5-(1-amino-6-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)pyridin-2-yl)-4,5-dichlorophenol

470 93 (S)-1-amino-1′-(5-(5-methylthiophen- 2-yl)pyrazin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-6-ol

393 94 (S)-1′-(5-(1H-indol-7-yl)pyrazin-2-yl)- 5-ethyl-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine

424 95 (S)-1′-(5-(cyclohex-1-en-1-yl)pyrazin- 2-yl)-5-isopropyl-1,3-dihydrospiro [indene-2,4′-piperidin]-1- amine

403 96 (S)-N-(1-amino-1′-(5-(2- (trifluoromethyl)phenyl)pyrimidin- 2-yl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-6-yl) methanesulfonamide

518 97 (S)-1′-(5-((4-(trifluoromethyl) pyrimidin- 5-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[c] pyridine-6,4′-piperidin]-7-amine

460 98 (S)-1′-(5-((2-chloropyridin-3-yl)thio) pyrazin-2-yl)-5,7-dihydrospiro[cyclo penta[c]pyridine-6,4′-piperidin]-5- amine

425 99 (S)-4-((5-(5-amino-5,7-dihydrospiro [cyclopenta[d]pyrimidine-6,4′- piperidin]-1′-yl)pyrazin-2-yl)thio)- 3-chlorobenzoic acid

469 100 (S)-1′-(5-((3-(trifluoromethyl)pyrazin- 2-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-7-amine

460 101 (S)-1′-(5-((3-chloropyridazin-4-yl)thio) pyrazin-2-yl)-5,7-dihydrospiro [cyclopenta[d]pyrimidine-6,4′- piperidin]-7-amine

427 102 (S)-4-((5-(5-amino-5,7-dihydrospiro [cyclopenta[b]pyrazine-6,4′- piperidin]-1′-yl)pyrazin-2-yl)thio)- 3-chlorobenzamide

468 103 (S)-(1-amino-1′-(5-((3-chloro-2- (methylamino)pyridin-4-yl)thio)pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-6-yl)dimethylphosphine oxide

529 104 (S)-1-amino-1′-(6-amino-5-((3-chloro- 2-(dimethylamino)pyridin-4-yl)thio) pyrazin-2-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-5-carboxylic acid

526 105 ethyl (S)-1-amino-1′-(5-((3-chloro-2- (methylamino)pyridin-4-yl)thio)pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-5-carboxylate

525 106 (S)-1′-(5-((3-(morpholinomethyl) phenyl)thio)pyrazin-2-yl)-6- (trifluoromethyl)-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine

556 107 (S)-6-bromo-5-fluoro-1′-(5-((3-(penta fluoro-16-sulfanyl)phenyl)thio)pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine

611 108 (S)-N-(3-((5-(1-amino-6-(methylthio)- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1′-yl)pyrazin-2-yl)thio)phenyl) cyclopropanecarboxamide

518 109 (S)-6-(6-amino-1-bromo-4H,6H-spiro [cyclopenta[c]thiophene-5,4′- piperidin]-1′-yl)-3-(m-tolyl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one

511 110 (S)-2-(1-amino-5,6,7-trifluoro-1,3- dihydrospiro[indene-2,4′-piperidin]-1′- yl)-5-(3-ethylphenyl)-3-methyl-3,7- dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one

508 111 (R)-1′-(3-(3-(tert-butyl)phenyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-3,4- dihydro-1H-spiro[naphthalene-2,4′- piperidin]-3-amine

467 112 (S)-2-(3-amino-1,3-dihydrospiro [cyclopenta[a]naphthalene-2,4′- piperidin]-1′-yl)-5-(3- isopropylphenyl)-3,7-dihydro-4H- pyrrolo[2,3-d]pyrimidin-4-one

504 113 (S)-1-amino-1′-(3-(3-chloro-2- morpholinopyridin-4-yl)-4-oxo-4,5- dihydro-1H-pyrrolo[3,2-c]pyridin-6- yl)-5-fluoro-1,3-dihydrospiro [indene-2,4′-piperidine]- 6-carbonitrile

574 114 (S)-1′-(7-(3-chloro-2-(cyclobutylamino) pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3- yl)-1,3-dihydrospiro[cyclopenta [a]naphthalene-2,4′-piperidin]- 3-amine

550 115 (S)-1′-(3-(3-chloro-2-(cyclopropylamino) pyridin-4-yl)-1H-pyrazolo[3,4-b] pyrazin-6-yl)-N6-methyl-1,3-dihydrospiro [indene-2,4′-piperidine]-1,6- diamine

516 116 (S)-5-amino-1′-(3-(3-chloro-2- (pyrrolidin-1-yl)pyridin-4-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-2-fluoro-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidine]-3-carboxamide

563 117 1-(4-(6-((S)-4-amino-2-chloro-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-3-chloropyridin-2-yl) pyrrolidin-3-ol

558 118 (S)-1′-(3-(3-chloro-2-((cyclopropyl- methyl)amino)pyridin-4-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-N6,N6- dimethyl-1,3-dihydrospiro[indene- 2,4′-piperidine]-1,6-diamine

544 119 (S)-1′-(3-(2-amino-6-chloropyridin- 4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 2-(tert-butyl)-4,6-dihydrospiro [cyclopenta[b]thiophene-5,4′- piperidin]-4-amine

509 120 (S)-2-chloro-1′-(3-(1,3-dihydroiso- benzofuran-5-yl)-1H-pyrazolo[3,4-b] pyrazin-6-yl)-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-6-amine

480 121 (S)-3-chloro-1′-(3-((2-chlorophenyl) thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-5-amine

498 122 (S)-1′-(3-(3-chloro-2-(ethylamino)pyridin- 4-yl)-1H-pyrazolo[3,4-b]pyrazin- 6-yl)-4,6-dihydrospiro[cyclopenta [b]thiophene-5,4′-piperidin]-4-amine

481 123 (R)-1′-(7-(methyl(pyridin-4-yl)amino)- 5H-pyrrolo[2,3-b]pyrazin-3-yl)-3H- spiro[furo[2,3-b]pyridine-2,4′- pipendin]-3-amine

429 124 (R)-1′-(3-((3-chloropyridin-4-yl) amino)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 6,7-dihydrospiro[cyclopenta[b] pyridine-5,4′-piperidin]-6-amine

448 125 (S)-2-methoxy-1′-(3-(1-phenylvinyl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole- 5,4′-piperidin]-4-amine

460 126 (R)-1-(3-benzyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)-1′,3′-dihydrospiro [piperidine-4,2′-pyrrolo[2,3-b] pyridin]-3′-amine

413 127 (S)-(6-(6-amino-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′-piperidin]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3- yl)(phenyl)methanone

432 128 (4S)-1′-(3-(1-phenylethyl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-4-amine

432 129 1-(6-((S)-5-amino-2-methoxy-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4- b]pyrazin-3-yl)-1-phenylethan-1-ol

472 130 (S)-1′-(3-((2,3-dichloropyridin-4-yl) oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-5-amine

483 131 (S)-6-bromo-1′-(3-(5-(3,4-difluorophenyl)- 3,4-dihydroquinolin-1(2H)-yl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine

642 132 (S)-6-amino-2-(1-amino-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-(4-cyclopropoxyphenyl)-3- methylpyrimidin-4(3H)-one

536 133 (S)-N-(1-amino-1′-(4-amino-5-((4- (methylthio)phenyl)thio)-6-oxo-1,6- dihydropyrimidin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-6-yl)acetamide

523 134 (S)-2-(1-amino-6-(methylamino)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-(4-(benzyloxy)phenyl)-3- methylpyrimidin-4(3H)-one

522 135 (S)-2-(7-acetyl-1-amino-1,3-dihydrospiro [indene-2,4′-piperidin]-1′-yl)-5- (benzo[d][1,3]dioxol-4-ylthio) pyrimidin-4(3H)-one

491 136 4-amino-6-((1S)-1-amino-7-(1- hydroxyethyl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-1′-yl)-3-(4- (difluoromethoxy)phenyl)-1- methylpyridin-2(1H)-one

511 137 (S)-1-amino-1′-(4-amino-6-oxo-5-(4- phenoxyphenyl)-1,6-dihydropyridin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-4-carbonitrile

504 138 (S)-6-(1-amino-4-hydroxy-1,3-dihydrospiro [indene-2,4′-piperidin]-1′-yl)-3- (4-cyclohexylphenyl)-1-methylpyridin- 2(1H)-one

484 139 (S)-3-([1,1′-biphenyl]-4-yl)-6-(1- amino-4-methoxy-1,3-dihydrospiro [indene-2,4′-piperidin]-1′-yl) pyridin-2(1H)-one

478 140 (S)-6-amino-2-(1-amino-6-(2-oxopiperidin- 1-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-3-methyl-5-(4- (trifluoromethoxy)phenyl)pyrimidin- 4(3H)-one

583 141 (S)-1-(1-amino-1′-(4-amino-5-((4- cyanophenyl)thio)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-6-yl)urea

517 142 (S)-4-amino-6-(1-amino-6-chloro-5- fluoro-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1-methyl-3-(4- (tetrahydro-2H-pyran-4-yl)phenyl)pyridin- 2(1H)-one

537 143 (S)-6-(1-amino-6-(trifluoromethyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1′- yl)-3-(4-(2-methoxyethoxy)phenyl)-1- methylpyridin-2(1H)-one

528 144 (S)-6-amino-2-(1-amino-6-(piperidine-1- carbonyl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-1′-yl)-3-methyl-5- (quinolin-8-ylthio)pyrimidin-4(3H)-one

596 145 (S)-6-amino-2-(1-amino-6-morpholino- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-3-methyl-5-((4-nitrophenyl)thio) pyrimidin-4(3H)-one

564 146 (S)-6-amino-2-(5-amino-3-nitro-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-3-methyl-5-(quinolin-8- ylthio)pyrimidin-4(3H)-one

531 147 (S)-6-(5-amino-3-(4-methylpiperazin-1- yl)-5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-1′-yl)-1- methyl-3-(naphthalen-1-ylthio) pyridin-2(1H)-one

567 148 (S)-2-(1-amino-6-(1H-pyrrol-1-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-((2,2-difluorobenzo[d][1,3] dioxol-4-yl)thio)pyrimidin-4(3H)-one

550 149 (S)-7-(5-(1-amino-6-(1H-imidazol-1- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-6-(hydroxymethyl)-3- methylpyrazin-2-yl)isoindolin-1-one

522 150 (S)-3-(1-amino-6-(ethylamino)-1,3- dihydrospiro[indene-2,4′-piperidin]-1′- yl)-6-(1H-indol-5-yl)-5-methylpyrazine-2- carboxamide

496 151 (S)-N-(1-amino-1′-(3-bromo-5-(1H- indol-6-yl)-6-methylpyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 6-yl)cyclopropanecarboxamide

571 152 (S)-4-(6-amino-5-(1-amino-4-methoxy- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-3-methylpyrazin-2-yl)-1,3- dihydro-2H-benzo[d]imidazol-2-one

472 153 (S)-3-(1-amino-5-methoxy-1,3- dihydrospiro [indene-2,4′-piperidin]-1′-yl)- 5-methyl-6-(2-oxoindolin-7-yl)pyrazine- 2-carbonitrile

481 154 (S)-N-(5-(1-amino-7-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-6-((2-hydroxyethyl)amino)-3- methylpyrazin-2-yl)benzenesulfonamide

539 155 (S)-1′-(6-methyl-3-(1H-pyrazol-5-yl)- 5-(1H-pyrrolo[2,3-b]pyridin-4-yl) pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta [b]pyridine-6,4′-piperidin]-5-amine

478 156 (S)-2-(3-(5-amino-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′-piperidin]- 1′-yl)-6-(8-chlorochroman-7-yl)-5- methylpyrazin-2-yl)propan-2-ol

520 157 (S)-6-chloro-1′-(5-(7-chloro-2,3- dihydrobenzofuran-6-yl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine

467 158 (S)-4-bromo-1′-(5-(3-(1-methyl-1H- pyrazol-5-yl)phenyl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine

515 159 (S)-1-amino-1′-(6-cyano-5-(1H-indazol- 7-yl)pyrazin-2-yl)-5-fluoro-1,3- dihydrospiro [indene-2,4′-piperidine]-6- carboxamide

483 160 (S)-1′-(5-(1H-indol-3-yl)-6-iodopyrazin- 2-yl)-5,7-dihydrospiro[cyclopenta [b]pyridine-6,4′-piperidin]-5-amine

523 161 (R)-6-(5-(7′-amino-7′,8′-dihydro-5′H- spiro[piperidine-4,6′-quinolin]-1-yl)- 3-vinylpyrazin-2-yl)isoindolin-1-one

453 162 (R)-1-(4-(5-(6-amino-6,7-dihydrospiro [cyclopenta[b]pyridine-5,4′-piperidin]- 1′-yl)-3-ethylpyrazin-2-yl)-3,3- difluoroindolin-1-yl)ethan-1-one

505 163 (S)-1′-(5-(3-methyl-1H-indazol-6-yl)- 6-phenylpyrazin-2-yl)-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′- piperidin]-5-amine

488 164 (S)-1′-(5-(1H-benzo[d][1,2,3]triazol- 6-yl)-6-cyclopropylpyrazin-2-yl)-6- ((tetrahydro-2H-pyran-4-yl)oxy)-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine

538 165 (S)-1-amino-1′-(3-((l-methyl-1H- imidazol-2-yl)thio)-1H-pyrazolo[3,4-b] pyrazin-6-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carbonitrile

458 166 (S)-1′-(3-(1H-benzo[d]imidazol-1-yl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-6- bromo-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine

515 167 (S)-1-(6-(1-amino-5-chloro-6-methoxy- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-3,4-dihydro-1,5- naphthyridin-2(1H)-one

531 168 (1-(6-((S)-1-amino-6-(methylthio)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5- naphthyridin-4-yl)methanol

529 169 1-(6-((1S)-1-amino-6-(methylsulfinyl)-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-5- fluoro-1,2,3,4-tetrahydroquinoline- 6-carbonitrile

557 170 (S)-6-chloro-1′-(3-(2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-5-methyl-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine

487 171 (S)-5-(6-(1-amino-4-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N- (2-methoxyethyl)-5,6,7,8-tetrahydro-1,5- naphthyridine-2-carboxamide

584 172 (S)-1-amino-5-fluoro-1′-(3-(6-(piperazin- 1-yl)-3,4-dihydro-1,5-naphthyridin- 1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin- 6-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carbonitrile

580 173 (S)-2-(1-(6-(1-amino-6-(methylthio)- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin- 5-yl)thiazole-4-carboxylic acid

625 174 (S)-1′-(6-(aminomethyl)-5-(2,3- dichloropyridin-4-yl)pyrazin-2-yl)-6- (1H-imidazol-1-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine

521 175 (1S)-1-amino-1′-(5-(2,3-dichloropyridin- 4-yl)-3-(2-(hydroxymethyl)pyrrolidine- 1-carbonyl)-6-methylpyrazin-2-yl)-N,N- dimethyl-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carboxamide

638 176 (S)-1′-(8-(2-amino-3-chloropyridin-4- yl)-7-methylimidazo[1,2-c]pyrimidin- 5-yl)-5-fluoro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine

478 177 (S)-1′-(5-(1-methyl-1H-indol-2-yl) pyrazin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-3,3-d2-1- amine

410 178 (S)-1-(6-(5-amino-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-1H-pyrazolo [3,4-b]pyrazin-3-yl)-1,2,3,4- tetrahydro-6H-pyrido[1,2-a] pyrimidin-6-one

470 179 (S)-1′-(3-(2,3,4,5-tetrahydro-1H- benzo[b]azepin-1-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclo penta[c]pyridine-6,4′-piperidin]-5- amine

467 180 (3-((S)-1-amino-6-fluoro-1,3-dihydro spiro[indene-2,4′-piperidin]-1′-yl)-6- ((R)-1-methylisoindolin-2-yl) pyrazin-2-yl)methanol

460 181 (S)-1′-(3-(6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro [cyclopenta[c]pyridine-6,4′- piperidin]-5,5-d2-7-amine

443 182 (S)-4-(difluoromethyl)-1′-(5-methyl- 6-((R)-2-methyl-3,4-dihydro-1,5- naphthyridin- 1(2H)-yl)pyridin-3-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine

470 183 (S)-1′-(8-(2-chloro-3-(isopropyl(methyl) amino)phenyl)-[1,2,4]triazolo[4,3-c] pyrimidin-5-yl)-2,3,6,8-tetrahydrospiro [indeno[5,6-b][1,4]dioxine- 7,4′-piperidin]-6-amine

561 184 (S)-1-(5-amino-1′-(8-((5-chloro-1- methylindolin-6-yl)thio)imidazo[1,5- a]pyridin-5-yl)-2,3,5,7-tetrahydro-1H- spiro[cyclopenta[b]pyrrolo[3,2-e] pyridine-6,4′-piperidin]-1-yl) ethan-1-one

601

Example A. Phosphatase Assay (Single Dose Inhibition) Assay Protocol:

For single dose inhibition assays using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as a substrate, SHP2 samples (diluted to 0.5 nM in reaction buffer) were incubated with dPEG8 peptide for 30 min in reaction buffer[60 mM 3,3-dimethyl glutarate (pH7.2), 75 mM NaCl, 75 mM KCl, and 1 mM EDTA, 0.05% Tween 20, 2mM dithiothreitol (DTT) ] to active the PTP. DMSO [0.5% (v/v)] or compounds (20nM) were added to the mixture and incubated for 30 min at room temperature. Reactions were initiated by the addition of DiFMUP (12 μM; total reaction volume of 100 μL), and the fluorescence (excitation at 340 nm, emission at 450 nm) of the resulting solutions was measured on a 2104-0020 EnVision Xcite Multilabel Reader (PerkinElmer) after 30min. The experiment is carried out in triplicate. The value for the control sample (DMSO) was set to 100%, and the values for the compound-treated samples were expressed as activity relative to the control sample. The inhibition of SHP2 by compounds of the invention were shown in table 1.

Example SHP2 inhibition(%)  1@0.02 μM 82  2@0.02 μM 80  3@0.02 μM 81  4@0.02 μM 89  5@0.02 μM 84  6@0.02 μM 89  8@0.02 μM 68 15@0.02 μM 64 19@0.02 μM 61 21@0.02 μM 68 23@0.02 μM 85 24@0.02 μM 87 25@0.02 μM 78 26@0.02 μM 67 27@0.02 μM 79 28@0.02 μM 74 29@0.02 μM 68 30@0.02 μM 80 31@0.02 μM 82 32@0.02 μM 75 33@0.02 μM 70 36@0.02 μM 88 37@0.02 μM 68 38@0.02 μM 53 39@0.02 μM 78 40@0.02 μM 68 45@0.02 μM 78 47@0.02 μM 56 50@0.02 μM 86 

What is claimed is:
 1. A compound of formula I or a pharmaceutically acceptable salt thereof:

Wherein, ring A is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted; ring B is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; T is absent, O, NR₁ or CR₁R₂; each of R₁ and R₂ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or R_(I) and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅; p is 0, 1, 2, 3 or 4; each of R₃ and R₄ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR₅, and each of the ring systems is independently optionally substituted or unsubstituted; each of R₅ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy; q is 0, 1, 2, 3 or 4; W is absent, O, S or —C(R_(W))₂-; and each of R_(W) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, —C₁₋₆alkylene-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when ring C is absent, Y₅ is CR_(5a)R_(5b), NR_(5a) or O, and Y₆ is CR_(6a)R_(6b), NR_(6a) or O; when ring C is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring; i) Y₅ is CR_(5a) or N, and Y₆ is CR_(6a) or N, when the “

” in the term “Y₅

Y₆” represents a single bond; or ii) Y₅ is C, and Y₆ is C, when the “

” in the term “Y₅

Y₆” represents a double bond; each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; each of R_(a) is independently selected from hydrogen, deuterium, halogen, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₆alkoxy, —C₁₋₆alkyl, —C₃₋₈cycloalkyl, —C₁₋₆alkylene—NR_(a1)R_(a2), —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₆alkylene-(3-10 membered heterocyclic), —C₁₋₆alkylene-(5-10 membered heteroaryl), —C₁₋₆alkylene—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(a1)—CO—C₁₋₆alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₁₀carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C₁₋₆alkyl, —CO—C₁₋₆alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C₁₋₆alkylene—CO—OR_(a1), —O—C₁₋₆alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₆alkylene—NR_(a1)R_(a2), —O—C₃₋₁₀carbocyclic, —O-(3-10 membered heterocyclic), —NR_(a1)—CO—C₁₋₆alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-10 membered heteroaryl), —NR_(a1)—CO—C₃₋₈cycloalkyl,—NR_(a1)—C₁₋₆alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₆alkylene-(3-10 membered heterocyclic), —NR_(a1)—C₁₋₆alkylene-(5-10 membered heteroaryl), —NR_(a1)—SO₂C₁₋₆alkyl, —S—C₁₋₆alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₆alkyl, —SO₂—C₁₋₆alkyl, —PO(C₁₋₆alkyl)₂, —PO(C₁₋₆alkoxy)₂,−3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n iso, 1, 2, 3, 4, 5 or 6; or two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; or R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted; each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein ring A is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 3. The compound or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein ring A is a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein ring A is a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 5. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein ring A is

represents a single bond or a double bond; X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X1) and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene-C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X2) and R_(X3) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ; X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or a 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X3) and R_(X4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X4) and R_(X5) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X5) and R_(X6) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted.
 6. The compound or pharmaceutically acceptable salt thereof of claim 5, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 7. The compound or pharmaceutically acceptable salt thereof of claim 5 or claim 6, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 8. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-7, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 9. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-8, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 10. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-9, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 11. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-10, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene-C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 12. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-11, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene-C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 13. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-12, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂,CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₄alkyl, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene-C₃₋₆cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 14. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-13, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene-C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 15. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-14, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 16. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-15, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 17. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-16, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 18. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-17, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.
 19. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-18, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene-C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 20. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-19, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl,—O—C₁₋₆alkylene-C₁₋₆alkyl, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 21. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-20, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₃alkyl, —C₁₋₃alkoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene-C₁₋₃alkyl, —O—C₅₋₆aryl or —O—C₁₋₃alkylene-C₅₋₆aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 22. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-21, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3;) each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene-C₁₋₃alkyl, —O—C₅₋₆aryl or —O—C₁₋₃alkylene-C₅₋₆aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 23. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-22, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, -S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene—C₁₋₃alkyl, —O—C₅₋₆aryl or —O—C₁₋₃alkylene-C₅₋₆aryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 24. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-23, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 25. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-24, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 26. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-25, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, an 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.
 27. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-26, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 28. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-27, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 29. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-28, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 30. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-29, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 31. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-30, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 32. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-31, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 33. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-32, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 34. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-33, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 35. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-34, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 36. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-35, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or -C₁₋₃alkoxy.
 37. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-36, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 38. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-37, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 39. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-38, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 40. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-39, wherein R_(X4) and R_(X5)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 41. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-40, wherein R_(X4) and R_(X5)together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 42. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-41, wherein R_(X4) and R_(X5) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 43. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-42, wherein X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 44. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-43, wherein X₆ is O, S, CO or NR_(X6,) or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 45. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-44, wherein X₆ is O, S, CO or NR_(X6,) or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 46. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-45, wherein X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 47. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-46, wherein X₆ is O, S, CO or NR_(X6), or C(R_(X6))₂; each of R_(X6) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 48. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-47, wherein R_(X5) and R_(X6) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 49. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-48, wherein R_(X5) and R_(X6) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 50. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-49, wherein R_(X5) and R_(X6) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 51. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-50, wherein ring A is selected from


52. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-51, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted.
 53. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-52, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted or unsubstituted.
 54. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-53, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.
 55. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-54, wherein ring B is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2,3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3, 4, 5 or 6heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 56. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-55, wherein ring B is a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2,3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 57. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-56, wherein ring B is a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, a 7 membered carbocyclic ring, a 8 membered carbocyclic ring, a 9 membered carbocyclic ring, a 10 membered carbocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, a 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 58. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-57, wherein ring B is

Y₁ is N or CR_(Y1), R_(Y1) is selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —N—(C₁₋₆alkyl)₂, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —N—(C₁₋₆alkyl)₂, alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(Y1)and R_(Y2)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when the “

” in the term “Y₃

Y₄” represents a single bond, Y₃ is NR_(Y3) or C(R_(Y3))₂, and Y₄ is CO, C(R_(Y4))₂ or NR_(Y4); when the “

” in the term “Y₃

Y₄” represents a double bond, Y₃ is N or CR_(Y3), and Y₄ is N or CR_(Y4); R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with —OH, or —C₁₋₆alkoxy; or R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted.
 59. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-58, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 60. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-59, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 61. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-60, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 62. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-61, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, I, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 63. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-62, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 64. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-63, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 65. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-64, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 66. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-65, wherein Y₂ is N or CR_(Y2); Rye is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 67. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-66, wherein R_(Y1) and R_(Y2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 68. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-67, wherein R_(Y1) and R_(Y2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 69. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-68, wherein R_(Y1)and R_(Y2)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 70. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-69, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —C₁₋₆alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with —OH or —C₁₋₆alkoxy.
 71. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-70, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —C₁₋₆alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl, —C₁₋₃alkyl substituted with —OH or —C₁₋₃alkoxy.
 72. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-71, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl, —C₁₋₃alkyl substituted with —OH or —C₁₋₃alkoxy.
 73. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-72, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CO—C₃₋₈heterocyclic ring, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, ethyl substituted with —OH, methoxy, ethoxy, propoxy or isopropoxy.
 74. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-73, wherein R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 75. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-74, wherein R_(Y3) and R_(Y4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 76. The compound or pharmaceutically acceptable salt there of any one of claims 1-75, wherein R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 77. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-75, wherein ring B is selected from


78. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-77, wherein each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 79. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-78, wherein each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 80. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-79, wherein each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 81. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-80, wherein each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 82. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-81, wherein R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR_(5.)
 83. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-82, wherein R₁ and R₂ together with the carbon atom to which they are both attached form CO.
 84. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-83, wherein R₁ and R₂ together with the carbon atom to which they are both attached form C═NR_(5.)
 85. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-84, wherein each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 86. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-85, wherein each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 87. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-86, wherein each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 88. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-87, wherein each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 89. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-88, wherein R₃ and R₄ together with the carbon atom to which they are both attached form 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 90. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-89, wherein R₃ and R₄ together with the carbon atom to which they are both attached form 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 91. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-90, wherein R₃ and R₄ together with the carbon atom to which they are both attached form 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, 9 membered heterocyclic ring, 10 membered heterocyclic ring, 5 membered heteroaromatic ring, 6 membered heteroaromatic ring, 7 membered heteroaromatic ring, 8 membered heteroaromatic ring, 9 membered heteroaromatic ring, 10 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 92. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-91, wherein each of R₅ is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 93. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-92, wherein each of R₅ is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 94. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-93, wherein each of R₅ is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy
 95. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-94, wherein W is absent, —O, —S or —C(R_(W))₂-; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, —C₁₋₆alkylene-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 96. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-95, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₃alkyl, —CO—OC₁₋₃alkyl, —C₁₋₃alkylene-O—C₁₋₃alkoxy, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 97. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-96, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkylene-O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 98. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-97, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkylene-O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 99. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-98, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkylene-O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 100. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-99, wherein ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 101. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-100, wherein ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 102. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-101, wherein ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 103. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-102, wherein ring C is selected from


104. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-103, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 105. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-104, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 106. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-105, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 107. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-106, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 108. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-107, wherein each of RY₆, and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 109. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-108, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 110. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-109, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 111. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-110, wherein each of Rha and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 112. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-111, wherein each of R_(a) is independently hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₃alkoxy,—C₁₋₄alkyl, —C₃₋₆cycloalkyl, —C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −5-8 membered heteroaryl, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR-(3-8 membered heterocyclic), —CO—NR-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene—CO—OR_(a1), —O—C₁₋₃alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene—NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂C₁₋₃alkyl, —S—C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or
 6. 113. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-112, wherein each of R_(a) is independently hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, butyl, isobutyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene—CO—OR_(a1), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −5-8 membered heteroaryl, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR-(3-8 membered heterocyclic), —CO—NR-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene—CO—OR_(a1), —O—C₁₋₃alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene-NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, -NL1—CO—NR_(a1)R_(a2), -NL1—CO-(5-8 membered heteroaryl), -NLI—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂C₁₋₃alkyl, —S—C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, −50₂—C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or
 6. 114. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-113, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 115. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-114, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 116. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-115, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 117. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-116, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 118. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-117, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, -C₁₋₃alkyl or —C₁₋₃alkoxy.
 119. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-118, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 120. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-116, R_(a) and R_(w) with the atom to which they are both attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 5 membered heteroaryl ring, a 6 membered heteroaryl ring, a 5 membered heterocyclic ring or a 6 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 121. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-120, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted -C₁₋₆alkyl.
 122. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-121, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 123. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-122, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 124. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-123, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 125. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-124, wherein the compound is of Formula II:

X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF_(S), —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X1) and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene-C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X2) and R_(X3) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ; X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl,-C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X3) and R_(X4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X4) and R_(X5) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

represents a single bond or a double bond; G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted; Y₁ is N or CR_(Y1), R_(Y1) is selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(Y1) and R_(Y2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when the “

” in the term “Y₃

Y₄” represents a single bond, Y₃ is NR_(Y3) or C(R_(Y3))₂, and Y₄ is CO, C(R_(Y4))₂ or NR_(Y4); when the “

” in the term “Y₃

Y₄” represents a double bond, Y₃ is N or CR_(Y3), and Y₄ is N or CR_(Y4); R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH , —C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; T is absent, O, NR₁ or CR₁R₂; each of R₁ and R₂ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅; p is 0, 1, 2 or 3; each of R₃ and R₄ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR₅, and each of the ring systems is independently optionally substituted or unsubstituted; each of R₅ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy; q is 0, 1, 2, 3 or 4; W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when ring C is absent, Y₅ is CR_(5a)R_(5b), NR_(5a) or O, and Y₆ is CR_(6a)R_(6b), NR_(6a) or O; when ring C is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring; i) Y₅ is CR_(5a) or N, and Y₆ is CR_(6a) or N, when the “

” in the term “Y₅

Y₆” represents a single bond; or ii) Y₅ is C, and Y₆ is C, when the “

” in the term “Y₅

Y₆” represents a double bond; each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; each of R_(a) is independently hydrogen, deuterium, halogen, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₆alkoxy, —C₁₋₆alkyl, —C₃₋₈cycloalkyl,-C₁₋₆alkylene—NR_(a1)R_(a2), —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₆alkylene-(3-10 membered heterocyclic), —C₁₋₆alkylene-(5-10 membered heteroaryl), —C₁₋₆alkylene—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁,₆alkylene—NR_(a1)—CO—C₁₋₆alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₁₀carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C₁₋₆alkyl, —CO—C₁₋₆alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C₁₋₆alkylene—CO—OR_(a1), —O—C₁₋₆alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₆alkylene—NR_(a1)R_(a2), —O—C₃₋₁₀carbocyclic, —O-(3-10 membered heterocyclic), —NR_(a1)—CO—C₁₋₆alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-10 membered heteroaryl), —NR_(a1)—CO—C₃₋₈cycloalkyl,—NR_(a1)—C₁₋₆alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₆alkylene-(3-10 membered heterocyclic), —NR_(a1)—C₁₋₆alkylene-(5-10 membered heteroaryl), —NR_(a1)—SO₂C₁₋₆alkyl, —S—C₁₋₆alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₆alkyl, —PO(C₁₋₆alkyl)₂, —PO(C₁₋₆alkoxy)₂, −3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 126. The compound or pharmaceutically acceptable salt thereof of claim 125, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 127. The compound or pharmaceutically acceptable salt thereof of claim 122 or claim 126, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 128. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-127, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 129. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-128, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 130. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-129, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 131. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-130, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SFS, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene-C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 132. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-131, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene-C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 133. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-132, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene—C₃₋₆cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 134. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-133, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene-C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 135. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-134, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene-C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 136. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-135, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 137. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-137, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 138. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-137, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.
 139. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-138, wherein X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3;) each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl,—O—C₁₋₆alkylene-C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 140. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-139, wherein X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₆alkylene-C₁₋₆alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 141. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-140, wherein X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₃alkyl, —C₁₋₃alkoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl, —O—C₁₋₃alkylene-C₁₋₃alkoxy, —O—C₅₋₈aryl or —O—C₁₋₆alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 142. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-141, wherein X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, -S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene—C₁₋₃alkoxy, −0—C₅₋₈aryl or —O—C₁₋₃alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 143. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-142, wherein X₃ is N, S, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, -S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene-C₁₋₃alkoxy, —O—C₅₋₈aryl or —O—C₁₋₃alkylene-C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 144. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-143, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 145. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-144, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 146. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-145, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.
 147. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-146, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 148. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-147, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 149. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-148, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 150. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-149, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 151. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-150, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 152. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-151, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 153. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-152, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 154. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-153, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 155. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-154, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 156. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-155, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 157. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-156, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 158. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-157, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 159. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-158, wherein X₅ is N, S, NR_(X5), C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 160. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-159, wherein R_(X4) and R_(X5) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 161. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-160, wherein R_(X4) and R_(X5) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 162. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-161, wherein R_(X4) and R_(X5) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 163. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-162, wherein ring A is selected from


164. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-163, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—,

—NR_(G)—SO₂—, —C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted.
 165. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-164, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted or unsubstituted.
 166. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-165, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.
 167. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-166, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C_(s-m)aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 168. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-167, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 169. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-168, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 170. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-169, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 171. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-170, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 172. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-171, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 173. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-172, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 174. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-173, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 175. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-174, R_(Y1) and R_(Y2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 176. The compound or pharmaceutically acceptable salt thereof of any one of claims 122-172, R_(Y1) and R_(Y2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 177. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-176, R_(Y1) and R_(Y2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 178. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-177, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 179. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-178, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH, —C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 180. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-179, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 181. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-180, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH, —C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 182. The compound or pharmaceutically acceptable salt thereof of any one claims 125-181, wherein R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 183. The compound or pharmaceutically acceptable salt thereof of any one claims 125-182, wherein R_(Y3) and R_(Y4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 184. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-183, wherein R_(Y3) and R_(Y4)together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 185. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-184, wherein ring B is selected from


186. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-185, wherein each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 187. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-186, wherein each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 188. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-187, wherein each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 189. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-188, wherein each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 190. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-189, wherein R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅.
 191. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-190, wherein R₁ and R₂ together with the carbon atom to which they are both attached form CO.
 192. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-191, wherein R₁ and R₂ together with the carbon atom to which they are both attached form C═NR₅.
 193. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-192, wherein each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 194. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-193, wherein each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 195. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-194, wherein each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 196. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-195, wherein each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 197. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-196, wherein R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 198. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-197, wherein R₃ and R₄ together with the carbon atom to which they are both attached form a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 199. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-198, wherein R₃ and R₄ together with the carbon atom to which they are both attached form a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 200. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-199, wherein each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 201. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-200, wherein each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 202. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-201, wherein each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy
 203. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-202, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 204. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-203, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₃alkyl, —CO—OC₁₋₃alkyl, —C₁₋₃alkyl—O—C₁₋₃alkoxy, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 205. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-204, wherein W is absent, —O, —S or —C(R_(W))₂-; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl—O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 206. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-205, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl—O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 207. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-206, wherein W is absent, —O, —S or —C(R_(W))₂-; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl—O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 208. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-207, wherein ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 209. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-208, wherein ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 210. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-209, wherein ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, a 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 211. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-210, wherein ring C is selected from


212. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-211, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 213. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-212, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 214. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-213, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 215. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-214, wherein each of R_(sa) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 216. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-215, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 217. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-216, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 218. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-217, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 219. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-218, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 220. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-219, wherein each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₃alkoxy, —C₁₋₃alkyl, —C₃₋₆cycloalkyl, —C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene—CO—OR_(a1), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene-NR_(a1)—CO—C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −5-10 membered heteroaryl, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene-NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene-CO—OR_(a1), —O—C₁₋₃alkylene-CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene-NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, −0-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl, —NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂ C₁-₃alkyl, —S—C₁₋₃alkyl, —SO₂NR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or
 6. 221. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-220, wherein each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, —C₃₋₆cycloalkyl, —C₁₋₃alkylene-NR_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene-CO—OR_(a1), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—NR_(a1)—C—NR_(a1)R_(a2), —CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene-NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO-NR_(a1)-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene-CO—OR_(a1), —O—C₁₋₃alkylene-CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene-NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, −O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, -NIU-00-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂C₁₋₃alkyl, —S—C₁₋₃alkyl, —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or
 6. 222. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-221, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 223. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-222, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 224. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-223, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 225. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-224, wherein each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted -C₁₋₆alkyl.
 226. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-225, wherein each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 227. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-226, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 228. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-227, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 229. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-228, wherein the compound is of Formula II-a:

Wherein X₁, X₂, X₃, X₄, X₅; G, R_(Y1), R_(Y3), T, R₃, R₄, W, Y₅; Y₆, R_(a), p, q and n are as defined in claims 125-228.
 230. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-229, wherein the compound is of Formula II-b

Wherein X₁, X₂, X₃, X₄, X₅; G, R_(Y1), R_(Ya), T, R₃, R₄, W, Y₅; Y₆, R_(a), p, q and n are as defined in claims 125-228.
 231. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-230, wherein the compound is of Formula II-c

Wherein X₁, X₂, X₃, X₄, X₅; G, R_(Y1), R_(Y2), R_(Ya), T, R₃, R₄, W, Y₅; Y₆, R_(a), p, q and n are as defined in claims 125-228.
 232. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-124, wherein the compound is of Formula III:

X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is selected from hydrogen, deuterium, halogen, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl; X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X1) and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3); each of R_(X3) is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl,-C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl or —O—C₁₋₆alkylene-C₁₋₆alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X2) and R_(X3) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ; X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X3) and R_(X4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X₅ is N, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; or R_(X4) and R_(X5)together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted;

represents a single bond or a double bond; G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—, —NR_(G)—SO₂—,

—C(R_(G))₂— or —SO₂—NR_(G)—, each of R_(G) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted; Y₁ is N or CR_(Y1), R_(Y1) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; Y₂ is N or CR_(Y2), R_(Y2) is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy; when the “

” in the term “Y₃

Y₄” represents a single bond, Y₃ is NR_(Y3), and Y₄ is CO; when the “

” in the term “Y₃

Y₄” represents a double bond, Y₃ is N or CR_(Y3), and Y₄ is N or CR_(Y4); R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, halogen, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH ,-C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxyl; T is absent, O, NR₁ or CRIR₂; each of R₁ and R₂ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR₅; p is 0, 1, 2 or 3; each of R₃ and R₄ is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; or R₃ and R₄ together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR₅, and each of the ring systems is independently optionally substituted or unsubstituted; each of R₅ is selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy; q is 0, 1, 2, 3 or 4; W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when ring C is absent, Y₅ is CR_(5a)R_(5b), NR_(5a) or O, and Y₆ is CR_(6a)R_(6b), NR_(6a) or O; when ring C is 5-12 membered aromatic ring, 5-12 membered heteroaromatic ring or 5-12 membered heterocyclic ring; i) Y₅ is CR_(5a) or N, and Y₆ is CR_(6a) or N, when the “

” in the term “Y₅

Y₆” represents a single bond; or ii) Y₅ is C, and Y₆ is C, when the “

” in the term “Y₅

Y₆” represents a double bond; each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; each of R_(6.) and R_(6b) is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl; each of R_(a) is independently hydrogen, deuterium, halogen, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₆alkoxy, —C₁₋₆alkyl, —C₃₋₈cycloalkyl,-C₁₋₆alkylene—NR_(a1)R_(a2), —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₆alkylene—CO—OR_(a1), —C₁₋₆alkylene-(3-10 membered heterocyclic), —C₁₋₆alkylene-(5-10 membered heteroaryl), —C₁₋₆alkylene—CO—NR_(a1)R_(a2), —C₁₋₆alkylene⁻NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₆alkylene—NR_(a1)—CO—C₁₋₆alkyl, —CO—NR_(a1)R_(a2), —COO—C₁₋₆alkyl, —CO—CO—NR_(a1)R.₂, —C₃₋₁₀carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C₁₋₆alkyl, —CO—C₁₋₆alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO—NR_(a1)-(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C₁₋₆alkylene—CO—OR_(a1), —O—C₁₋₆alkylene—CO—NR_(a1)R.2,—O—C₁₋₆alkylene—NR_(a1)R_(a2), —O—C₃₋₁₀carbocyclic, —O-(3-10 membered heterocyclic), —NR_(a1)—CO—C₁₋₆alkyl, —NR_(a1)—CO—NR_(a1)R.₂, —NR—CO-(5-10 membered heteroaryl), —NR_(a1)—CO—C₃₋₈cycloalkyl,—NR_(a1)—C₁₋₆alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₆alkylene-(3-10 membered heterocyclic), —NR_(a1)—C₁₋₆alkylene-(5-10 membered heteroaryl), —NR_(a1)—SO₂C₁₋₆alkyl, —S—C₁₋₆alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₆alkyl, —SO₂C₁₋₆alkyl, —PO(C₁₋₆alkyl)₂, —PO(C₁₋₆alkoxy)₂, −3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or two adjacent R_(a) can be joined together to form a 6-membered aryl ring, 5-membered heteroaryl ring, 6-membered heteroaryl ring, −3-6 membered heterocyclic or -3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; or R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted; each of R_(a1)and R_(a)e is independently selected from hydrogen, deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 233. The compound or pharmaceutically acceptable salt thereof of claim 232, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 234. The compound or pharmaceutically acceptable salt thereof of claim 232 or claim 233, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 235. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-234, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 236. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-235, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 237. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-236, wherein X₁ is N, S, NR_(X1), C(R_(X1))₂, or CR_(X1); each of R_(X1) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CONH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 238. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-237, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene-C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 239. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-238 wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —CO—C₁₋₆alkyl, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —SF₅, —NHCO—C₃₋₈cycloalkyl, —NH—C₃₋₈cycloalkyl, —C₁₋₆alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C₁₋₆alkylene—C₃₋₈cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 240. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-239, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₄alkyl, —C₁₋₃alkoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene-C₃₋₆cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 241. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-240, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene-C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 242. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-241, wherein X₂ is N, S, NR_(X2), C(R_(X2))₂, CR_(X2) or CO; each of R_(X2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C₁₋₃alkyl, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —SF₅, —NHCO—C₃₋₆cycloalkyl, —NH—C₃₋₆cycloalkyl, —C₁₋₃alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C₁₋₃alkylene-C₃₋₆cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, -oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 243. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-242, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 244. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-243, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 245. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-244, wherein R_(X1) and R_(X2) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.
 246. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-245, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3;) each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl or —O—C₁₋₆alkylene-C₁₋₆alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 247. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-246, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3;) each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₅₋₈aryl, —S—C₁₋₆alkyl, 3-12 membered heterocyclyl, —O—C₃₋₈cycloalkyl or —O—C₁₋₆alkylene-C₁₋₆alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 248. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-247, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3;) each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, —C₁₋₃alkyl,—C₁₋₃alkoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, -S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene—C₁₋₃alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 249. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-248, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3;) each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene-C₁₋₃alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 250. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-249, wherein X₃ is N, S, O, NR_(X3), C(R_(X3))₂ or CR_(X3;) each of R_(X3) is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO₂, —NH₂, —CN, —CONH₂, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C₃₋₆cycloalkyl, C₅₋₈aryl, —S—C₁₋₃alkyl, 3-10 membered heterocyclyl, —O—C₃₋₆cycloalkyl or —O—C₁₋₃alkylene —C₁₋₃alkyl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 251. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-250, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 252. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-251, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 253. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-252, wherein R_(X2) and R_(X3) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.
 254. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-253, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 255. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-254, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 256. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-255, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl,—C₁₋₃alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 257. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-256, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 258. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-257, wherein X₄ is N, S, NR_(X4), C(R_(X4))₂ or CR_(X4); each of R_(X4) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, oxo, ═O, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 259. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-258, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 260. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-259, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 261. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-260, wherein R_(X3) and R_(X4) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 262. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-261, wherein X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 263. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-262, wherein X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 264. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-263, wherein X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 265. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-264, wherein X₅ is N, S, NR_(X5) C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 266. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-265, wherein X₅ is N, S, NR_(X5)C(R_(X5))₂ or CR_(X5); each of R_(X5) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 267. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-266, wherein R_(X4) and R_(X5) together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 268. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-267, wherein R_(X4) and R_(X5) together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 269. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-268, wherein R_(X4) and R_(X5) together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 270. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-269, wherein ring A is selected from


271. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-270, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independent selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy, and each of which is independently optionally substituted or unsubstituted.
 272. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-271, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—,

—C(R_(G))₂— or —SO₂—NR_(G)—; each of R_(G) is independent selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy, and each of which is independently optionally substituted or unsubstituted.
 273. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-272, wherein G is selected from absent, S, —SO—, —SO₂—, O, —CO—, —NR_(G)—,

—C(R_(G))₂— or −502—NR_(G)—; each of R_(G) is independent selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.
 274. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-273, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, -C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, -C₁₋₆alkyl or —C₁₋₆alkoxy.
 275. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-274, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆alkenyl, —C₃₋₈cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 276. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-275, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 277. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-276, wherein Y₁ is N or CR_(Y1); R_(Y1) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 278. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-277, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 279. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-278, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH—C₁₋₆alkyl, —N—(C₁₋₆alkyl)₂, —C₁₋₆ alkenyl, —C₃₋₈cycloalkyl or —C₅₋₁₀aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 280. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-279, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —C₁₋₃alkyl, —C₁₋₃alkoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 281. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-280, wherein Y₂ is N or CR_(Y2); R_(Y2) is selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C₁₋₃alkyl, —N—(C₁₋₃alkyl)₂, —C₁₋₃alkenyl, —C₃₋₆cycloalkyl or —C₅₋₈aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 282. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-281, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH , —C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 283. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-282, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₆alkyl, carboxyl, —COO—C₁₋₆alkyl, —NH—C₁₋₆alkylene—OH ,-C₁₋₆alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 284. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-283, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, —C₁₋₃alkyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH ,—C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 285. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-284, wherein R_(Y3) and R_(Y4) are independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C₁₋₃alkyl, —NH—C₁₋₃alkylene—OH ,—C₁₋₃alkylene—OH, —CONH₂ or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH₂, —CN, —OH, —NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 286. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-285, wherein ring B is selected from


287. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-286, wherein each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 288. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-287, wherein each of R₁ and R₂ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 289. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-288 wherein each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 290. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-289, wherein each of R₁ and R₂ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 291. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-290, wherein R₁ and R₂ together with the carbon atom to which they are both attached form CO or C═NR_(5.)
 292. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-291, wherein R₁ and R₂ together with the carbon atom to which they are both attached form CO.
 293. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-292, wherein R₁ and R₂ together with the carbon atom to which they are both attached form C═NR₅.
 294. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-293, wherein each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₆alkyl, —N(C₁₋₆alkyl)₂, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 295. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-294, wherein each of R₃ and R₄ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —NH—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted
 296. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-295 wherein each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 297. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-296, wherein each of R₃ and R₄ is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; —NH—C₁₋₃alkyl; —N(C₁₋₃alkyl)₂; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 298. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-297, wherein R₃ and R₄ together with the carbon atom to which they are both attached form 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 299. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-298, wherein R₃ and R₄ together with the carbon atom to which they are both attached form 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring or C═NR₅; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 300. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-299, wherein R₃ and R₄ together with the carbon atom to which they are both attached form 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, 9 membered heterocyclic ring, 10 membered heterocyclic ring, 5 membered heteroaromatic ring, 6 membered heteroaromatic ring, 7 membered heteroaromatic ring, 8 membered heteroaromatic ring, 9 membered heteroaromatic ring, 10 membered heteroaromatic ring or C═NR₅, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 301. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-300, wherein each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 302. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-301, wherein each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 303. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-302, wherein each of R₅ is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 304. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-303, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₆alkyl, —CO—OC₁₋₆alkyl, —C₁₋₆alkyl-O—C₁₋₆alkoxy, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 305. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-304, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —CO—C₁₋₃alkyl, —CO—OC₁₋₃alkyl, —C₁₋₃alkyl—O—C₁₋₃alkoxy, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl
 306. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-305, wherein W is absent, —O, —S or —C(R_(W))₂-; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl—O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 307. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-306, wherein W is absent, —O, —S or —C(R_(W))₂—; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl—O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 308. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-307, wherein W is absent, —O, —S or —C(R_(W))₂-; and each of R_(W) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN;—OH; —NO₂; carboxyl; —CO—C₁₋₃alkyl; —CO—OC₁₋₃alkyl; —C₁₋₃alkyl—O—C₁₋₃alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 309. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-308, wherein ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 310. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-309, wherein ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 311. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-310, wherein ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.
 312. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-311, wherein ring C is selected from


313. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-312, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 314. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-313, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 315. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-314, wherein each of R_(5a) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 316. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-315, wherein each of R_(Ya) and R_(5b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 317. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-316, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted —C₁₋₆alkyl.
 318. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-317, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 319. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-318, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 320. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-319, wherein each of R_(6a) and R_(6b) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 321. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-320, wherein each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R_(a2), —CN, —OH, —NO₂, oxo, ═O, carboxyl, —C₁₋₃alkoxy,—C₁₋₄alkyl, —C₃₋₆cycloalkyl, —C₁₋₃alkylene—NR_(a1)R_(a2), —C₁₋₃alkylene-O—C₁₋₆alkyl, —C₁₋₃alkylene—CO—OR_(a1), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), —C₁₋₃alkylene—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—NR_(a1)R_(a2), —C₁₋₃alkylene—NR_(a1)—CO—C₁₋₃alkyl, —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —COO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene-CO—OR_(a1), —O—C₁₋₃alkylene-CO—NR_(a1)R_(a2), ⁻0 ⁻C₁₋₃alkylene-NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO—NR_(a1)R_(a2), —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO—C₁₋₃alkyl, —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or
 6. 322. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-321, wherein each of R_(a) is independently selected from hydrogen, deuterium, F, Cl, Br, —NR_(a1)R.₂, —CN, —OH, —NO₂, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, butyl, isobutyl, —C₃₋₆cycloalkyl,-C₁₋₃alkylene⁻NR_(a1)R_(a2), —C₁₋₃alkylene-(3-8 membered heterocyclic), —C₁₋₃alkylene-(5-8 membered heteroaryl), -₃alkylene⁻CO⁻NR_(a1)R_(a2), -₃alkylene⁻NR_(a1) ⁻CO⁻NR_(a1)R_(a2), —CO—NR_(a1)R_(a2), —CO—CO—NR_(a1)R_(a2), —C₃₋₈carbocyclic, −3-8 membered heterocyclic, —CO—C₁₋₃alkyl, —CO—C₁₋₃alkylene—NR_(a1)R_(a2), —CO—NR.1-(3-8 membered heterocyclic), —CO—NR_(a1)-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C₁₋₃alkylene-CO—OR_(a1), —O—C₁₋₃alkylene—CO—NR_(a1)R_(a2), —O—C₁₋₃alkylene-NR_(a1)R_(a2), —O—C₃₋₈carbocyclic, —O-(3-8 membered heterocyclic), —NR_(a1)—CO—C₁₋₃alkyl, —NR_(a1)—CO-(5-8 membered heteroaryl), —NR_(a1)—CO—C₃₋₆cycloalkyl,—NR_(a1)—C₁₋₃alkylene—NR_(a1)R_(a2), —NR_(a1)—C₁₋₃alkylene-(3-8 membered heterocyclic), —NR_(a1)—C₁₋₃alkylene-(5-8 membered heteroaryl), —NR_(a1)—SO₂C₁₋₃alkyl, —SONR_(a1)R_(a2), —SO₂NR_(a1)R_(a2), —SO₂C₁₋₃alkyl, —PO(C₁₋₃alkyl)₂, —PO(C₁₋₃alkoxy)₂, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or
 6. 323. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-322, wherein each of R_(a1)and R_(a)e is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₆alkoxy, or substituted or unsubstituted
 324. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-323, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 325. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-324, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 326. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-325, wherein two adjacent R_(a) can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 327. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-326, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, halogen, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₆alkyl or —C₁₋₆alkoxy.
 328. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-327, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 329. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-328, R_(a) and R_(w) with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 330. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-329, R_(a) and R_(w) with the atom to which they are both attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 5 membered heteroaryl ring, a 6 membered heteroaryl ring, a 5 membered heterocyclic ring or a 6 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, —C₁₋₃alkyl or —C₁₋₃alkoxy.
 331. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-330, wherein each of R_(a1) and R_(a2) is independently selected from hydrogen, deuterium, F, Cl, Br, —NH₂, —CN, —OH, —NO₂, carboxyl, substituted or unsubstituted —C₁₋₃alkoxy, or substituted or unsubstituted —C₁₋₃alkyl.
 332. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-331, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with halogen, NH₂, CN, OH, NO₂, carboxyl, C₁₋₃alkyl or C₁₋₃alkoxy.
 333. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-332, wherein each of R_(a1)and R_(a2) is independently selected from hydrogen; deuterium; F; Cl; Br; —NH₂; —CN; —OH; —NO₂; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C₁₋₃alkoxy substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C₁₋₃alkyl substituted with F, Cl, Br, NH₂, CN, OH, NO₂, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
 334. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-333, wherein the compound is of Formula III-a:

Wherein X₁, X₂, X₃, X₄, X₅; G, R_(Y3), T, R₃, R₄, W, Y₅; Y₆, R_(a), p, q and n are as defined in claims 232-333.
 335. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-334, wherein the compound is of Formula III-b:

Wherein X₁, X₂, X₃, X₄, X₅; G, R_(Y3), T, R₃, R₄, W, Y₅; Y₆, R_(a), p, q and n are as defined in claims 232-334.
 336. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-335, wherein the compound is of Formula III-c:

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Y3), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined in claims 232-335.
 337. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-336, wherein the compound is of Formula III-d:

Wherein X₁, X₂, X₃, X₄, X₅; G, R_(Y3), T, R₃, R₄, W, Y₅; Y₆, R_(a), p, q and n are as defined in claims 232-336.
 338. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-337, wherein the compound is of Formula III-e:

Wherein X₁, X₂, X₃, X₄, X₅, G, R_(Ya), T, R₃, R₄, W, Y₅, Y₆, R_(a), p, q and n are as defined in claims 232-337.
 339. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-338, wherein the compound is selected from 1 ethyl (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5--2- carboxylate 2 (S)-1′-(5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 3 (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazine-2-carboxylic acid 4 (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylplyrazine-2-carboxamide 5 ethyl (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2-amino-3-chloropyridin- 4-yl)thio)-5-methylpyrazine-2-carboxylate 6 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2 4′-piperidin]-1-amine 7 (S)-1′-(6-amino-5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 8 (S)-1′-(4-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrimidin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 9 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 10 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-(methylamino)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 11 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-(dimethylamino)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 12 (S)-1′-(6-amino-5-(thiazol-4-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 13 (S)-1′-(6-amino-5-(thiazol-2-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 14 (S)-1′-(6-amino-5-(quinolin-3-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 15 (S)-5-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-3-carbonitrile 16 (S)-1′-(5-((2-ammo-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-N-methyl-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine 17 (S)-1′-(5-((3,5-dichloropyridin-4-yl)thio)pyrazin-2-yl)-5,6,7-trifluoro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine 18 (S)-1-amino-1′-(2-((2-cyanopyridin-3-yl)thio)pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-4-carbonitrile 19 (S)-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)pyrazin-2-yl)-6-(methylthio)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 20 (S)-1-(5-((5-(4-amino-2-(tert-butyl)-4,6-dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-1′- yl)pyrazin-2-yl)thio)-2-chlorophenyl)ethan-1-one 21 (S)-1′-(5-((3-chloro-2-(isopropylamino)pyridin-4-yl)thio)pyrazin-2-yl)-6-(methylsulfonyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 22 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7,7-d2-5-amine 23 (S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazin-2-yl)methanol 24 (S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2-amino-3-chloropyridin-4- yl)thio)-5-methylpyrazin-2-yl)methanol 25 (S)-1′-(3-bromo-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 26 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazine-2-carbonitrile 27 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazine-2-carboxamide 28 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazin-2-ol 29 (S)-1′-(6-amino-3-bromo-5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 30 (S)-5-amino-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-((2,3- dichlorophenyl)thio)pyrazine-2-carbonitrile 31 (S)-5-amino-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-((2,3- dichlorophenyl)thio)pyrazine-2-carboxamide 32 (S)-1′-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 33 (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)pyridin-3-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 34 (S)-1′-(4-((2-amino-3-chloropyridin-4-yl)thio)phenyl)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 35 (S)-1′-(4-((2-amino-3-chloropyridin-4-yl)thio)isoquinolin-1-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 36 (S)-6-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-3-(2,3- dichlorophenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 37 (S)-6-(1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2,3-dichlorophenyl)- 5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 38 (S)-6-(1-amino-5,6,7-trifluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methyl-3-(5- methylthiophen-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 39 (S)-2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3- dichlorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 40 (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2-amino-3- chloropyridin-4-yl)thio)-3-methylpyrimidin-4(3H)-one 41 (S)-1′-(6-amino-5-((4-chlorothiazol-2-yl)thio)pyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 42 (S)-1-amino-1′-(5-((4-amino-5-bromopyrimidin-2-yl)thio)-1-methyl-6-oxo-1,6-dihydropyridin-2- yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 43 (S)-6-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-((3-chloro-2- methoxypyridin-4-yl)thio)-1-methylpyridin-2(1H)-one 44 (S)-1-amino-1′-(4-(6-bromonaphthalen-2-yl)thiazol-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-6-carbonitrile 45 (S)-1′-(6-amino-5-(2-chloro-3-methylphenyl)pyrazin-2-yl)-6-bromo-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 46 (S)-1′-(5-(3-amino-2-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-1,6-diamine 47 (S)-1′-(6-amino-5-(2-chloro-3-methylphenyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-1,6-diamine 48 (S)-1′-(6-(5-chlorothiophen-2-yl)pyridazin-3-yl)-5-methyl-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 49 (S)-1′-(6′-chloro-[3,3′-bipyridazin]-6-yl)-5-methyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1- amine 50 (S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 51 (R)-1′-(5-(2,3-dichloro-5-methoxyphenyl)pyridin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]- 2-amine 52 (S)-6′-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1′-methyl-2′-oxo-1′,2′- dihydro-[3,3′-bipyridine]-2-carbonitrile 53 (S)-6′-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1′-methyl-2′-oxo-1′,2′- dihydro-[3,3′-bipyridine]-2-carboxamide 54 (S)-1′-(4-(3-methoxyphenyl)cyclohexyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]- 5-amine 55 (S)-1-amino-1′-(6-((3-amino-2-chlorophenyl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carbonitrile 56 1-(5-((5-((1S)-1-amino-6-(methylsulfmyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin- 2-yl)thio)-2-chlorophenyl)ethan-1-one 57 (S)-1′-(5-(pyrimidin-2-ylthio)pyrazin-2-yl)-6-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 58 (S)-6-bromo-5-fluoro-1′-(5-(quinolin-4-ylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 59 (S)-6-(4-amino-4,6-dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-1′-yl)-3-(3- (trifluoromethyl)pyridin-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 60 (S)-2-(1-amino-6-chloro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3,5- dichloropyridin-4-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 61 (S)-1′-(7-(5-chloropyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-3-amine 62 (S)-1′-(7-(3-chloropyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1H,3H-spiro[phenalene-2,4′- piperidin]-1-amine 63 (R)-1′-(3-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3,4-dihydro-1H- spiro[naphthalene-2,4′-piperidin]-3-amine 64 (S)-6-amino-2-(1-amino-7-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methyl-5- phenylpyrimidin-4(3H)-one 65 (S)-1-amino-1′-(4-amino-6-oxo-5-(pyridazin-3-ylthio)-1,6-dihydropyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-7-carbonitrile 66 (S)-1-amino-1′-(1-methyl-6-oxo-5-(pyrazin-2-yl)-1,6-dihydropyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-7-carbonitrile 67 (S)-2-(1-amino-6-chloro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((4- isopropylphenyl)thio)pyrimidin-4(3H)-one 68 (S)-4-amino-6-(1-amino-6-bromo-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2- chloro-3-methylphenyl)-1-methylpyridin-2(1H)-one 69 (S)-6-(4-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-4-amino-3-(4- (trifluoromethyl)phenyl)pyridin-2(1H)-one 70 (S)-6′-(1-amino-4-hydroxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2′-oxo-1′,2′-dihydro- [3,3′-bipyridine]-2-carbonitrile 71 (S)-1′-(3-bromo-5-(1H-indol-6-yl)-6-methylpyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 72 (S)-3-(4-amino-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-5-methyl-6-(2- oxoindolin-7-yl)pyrazine-2-carbonitrile 73 (S)-1′-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 74 (S)-1′-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thio)pyridin-3-yl)-6-chloro-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 75 (S)-1′-(4-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 76 (S)-1′-(5-((2,3-dichlorophenyl)thio)thiazol-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-7-amine 77 (R)-1′-(4-((3-chloropyridin-4-yl)thio)thiazol-2-yl)spiro[indoline-2,4′-piperidin]-3-amine 78 (R)-1′-(2-(7-chloro-1H-indol-1-yl)thiazol-4-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-amine 79 (R)-1′-(2-((2-(trifluoromethyl)phenyl)thio)thiazol-5-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3- amine 80 (S)-(5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)(2,3- dichlorophenyl)methanone 81 (S)-2-(1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(indolin-1-yl)-3-methyl- 3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 82 (S)-1′-(5-((1,2,3,4-tetrahydroquinolin-8-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[b]naphthalene-2,4′-piperidin]-1-amine 83 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-1-amine 84 1′-(5-((3-amino-2-chlorophenyl)thio)-6-methylpyrazin-2-yl)-1-methyl-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 85 (R)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)-1H-indol-4-yl)-3H-spiro[benzofuran-2,4′- piperidin]-3-amine 86 (S)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)isoquinolin-3-yl)-5,6-dibromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 87 (S)-4-((5-(5-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-aminopyrazin-2- yl)thio)-3-chloro-1-methylpyridin-2(1H)-one 88 (S)-5-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-((2,3-dichlorophenyl)thio)- 6-(hydroxymethyl)pyridin-3-ol 89 (S)-6-bromo-1′-(5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 90 (S)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl)-6-bromo-1,3- dihydrospiroindene-2,4′-piperidin]-1-amine 91 (S)-1′-(8-((2-amino-3-chloropyridin-4-yl)thio)pyrido[4,3-d]pyrimidin-5-yl)-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 92 (S)-3-(5-(1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridin-2-yl)-4,5- dichlorophenol 93 (S)-1-amino-1′-(5-(5-methylthiophen-2-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]- 6-ol 94 (S)-1′-(5-(1H-indol-7-yl)pyrazin-2-yl)-5-ethyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 95 (S)-1′-(5-(cyclohex-1-en-1-yl)pyrazin-2-yl)-5-isopropyl-1,3-dihydrospiro[indene-2,4′-piperidin]- 1-amine 96 (S)-N-(1-amino-1′-(5-(2-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-6-yl)methanesulfonamide 97 (S)-1′-(5-((4-(trifluoromethyl)pyrimidin-5-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-amine 98 (S)-1′-(5-((2-chloropyridin-3-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′- piperidin]-5-amine 99 (S)-4-((5-(5-amino-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)-3-chlorobenzoic acid 100 (S)-1′-(5-((3-(trifluoromethyl)pyrazin-2-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-amine 101 (S)-1′-(5-((3-chloropyridazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[d]pyrimidine- 6,4′-piperidin]-7-amine 102 (S)-4-((5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyrazine-6,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)-3-chlorobenzamide 103 (S)-(1-amino-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-6-yl)dimethylphosphine oxide 104 (S)-1-amino-1′-(6-amino-5-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-5-carboxylic acid 105 ethyl (S)-1-amino-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-5-carboxylate 106 (S)-1′-(5-((3-(morpholinomethyl)phenyl)thio)pyrazin-2-yl)-6-(trifluoromethyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 107 (S)-6-bromo-5-fluoro-1′-(5-((3-(pentafluoro-16-sulfanyl)phenyl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 108 (S)-N-(3-((5-(1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)phenyl)cyclopropanecarboxamide 109 (S)-6-(6-amino-1-bromo-4H,6H-spiro[cyclopenta[c]thiophene-5,4′-piperidin]-1′-yl)-3-(m-tolyl)- 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 110 (S)-2-(1-amino-5,6,7-trifluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-ethylphenyl)-3- methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 111 (R)-1′-(3-(3-(tert-butyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3,4-dihydro-1H- spiro[naphthalene-2,4′-piperidin]-3-amine 112 (S)-2-(3-amino-1,3-dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-1′-yl)-5- (3-isopropylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 113 (S)-1-amino-1′-(3-(3-chloro-2-morpholinopyridin-4-yl)-4-oxo-4,5-dihydro-1H- pyrrolo[3,2-c]pyridin-6-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 114 (S)-1′-(7-(3-chloro-2-(cyclobutylamino)pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-3-amine 115 (S)-1′-(3-(3-chloro-2-(cyclopropylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N6- methyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1,6-diamine 116 (S)-5-amino-1′-(3-(3-chloro-2-(pyrrolidin-1-yl)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2- fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-3-carboxamide 117 1-(4-(6-((S)-4-amino-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-yl)pyrrolidin-3-ol 118 (S)-1′-(3-(3-chloro-2-((cyclopropylmethyl)amino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- N6,N6-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1,6-diamine 119 (S)-1′-(3-(2-amino-6-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-(tert-butyl)-4,6- dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-4-amine 120 (S)-2-chloro-1′-(3-(1,3-dihydroisobenzofuran-5-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-amine 121 (S)-3-chloro-1′-(3-((2-chlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 122 (S)-1′-(3-(3-chloro-2-(ethylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-4-amine 123 (R)-1′-(7-(methyl(pyridin-4-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-3H- spiro[furo[2,3-b]pyridine-2,4′-piperidin]-3-amine 124 (R)-1′-(3-((3-chloropyridin-4-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-6,7- dihydrospiro[cyclopenta[b]pyridine-5,4′-piperidin]-6-amine 125 (S)-2-methoxy-1′-(3-(1-phenylvinyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 126 (R)-1-(3-benzyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[piperidine-4,2′- pyrrolo[2,3-b]pyridin]-3′-amine 127 (S)-(6-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)(phenyl)methanone 128 (4S)-1′-(3-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 129 1-(6-((S)-5-amino-2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1-phenylethan-1-ol 130 (S)-1′-(3-((2,3-dichloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 131 (S)-6-bromo-1′-(3-(5-(3,4-difluorophenyl)-3,4-dihydroquinolin-1(2H)-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 132 (S)-6-amino-2-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(4- cyclopropoxyphenyl)-3-methylpyrimidin-4(3H)-one 133 (S)-N-(1-amino-1′-(4-amino-5-((4-(methylthio)phenyl)thio)-6-oxo-1,6-dihydropyrimidin-2-yl)- 1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)acetamide 134 (S)-2-(1-amino-6-(methylamino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(4- (benzyloxy)phenyl)-3-methylpyrimidin-4(3H)-one 135 (S)-2-(7-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(benzo[d][1,3]dioxol- 4-ylthio)pyrimidin-4(3H)-one 136 4-amino-6-((1S)-1-amino-7-(1-hydroxyethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- (4-(difluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one 137 (S)-1-amino-1′-(4-amino-6-oxo-5-(4-phenoxyphenyl)-1,6-dihydropyridin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile 138 (S)-6-(1-amino-4-hydroxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(4- cyclohexylphenyl)-1-methylpyridin-2(1H)-one 139 (S)-3-([1,1′-biphenyl]-4-yl)-6-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′- yl)pyridin-2(1H)-one 140 (S)-6-amino-2-(1-amino-6-(2-oxopiperidin-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- methyl-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4(3H)-one 141 (S)-1-(1-amino-1′-(4-amino-5-((4-cyanophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2- yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)urea 142 (S)-4-amino-6-(1-amino-6-chloro-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1- methyl-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)pyridin-2(1H)-one 143 (S)-6-(1-amino-6-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(4-(2- methoxyethoxy)phenyl)-1-methylpyridin-2(1H)-one 144 (S)-6-amino-2-(1-amino-6-(piperidine-1-carbonyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)- 3-methyl-5-(quinolin-8-ylthio)pyrimidin-4(3H)-one 145 (S)-6-amino-2-(1-amino-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methyl- 5-((4-nitrophenyl)thio)pyrimidin-4(3H)-one 146 (S)-6-amino-2-(5-amino-3-nitro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-3- methyl-5-(quinolin-8-ylthio)pyrimidin-4(3H)-one 147 (S)-6-(5-amino-3-(4-methylpiperazin-1-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-1-methyl-3-(naphthalen-1-ylthio)pyridin-2(1H)-one 148 (S)-2-(1-amino-6-(1H-pyrrol-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2,2- difluorobenzo[d][1,3]dioxol-4-yl)thio)pyrimidin-4(3H)-one 149 (S)-7-(5-(1-amino-6-(1H-imidazol-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6- (hydroxymethyl)-3-methylpyrazin-2-yl)isoindolin-1-one 150 (S)-3-(1-amino-6-(ethylamino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(1H-indol-5-yl)- 5-methylpyrazine-2-carboxamide 151 (S)-N-(1-amino-1′-(3-bromo-5-(1H-indol-6-yl)-6-methylpyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-6-yl)cyclopropanecarboxamide 152 (S)-4-(6-amino-5-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- methylpyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 153 (S)-3-(1-amino-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methyl-6-(2- oxoindolin-7-yl)pyrazine-2-carbonitrile 154 (S)-N-(5-(1-amino-7-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2- hydroxyethyl)amino)-3-methylpyrazin-2-yl)benzenesulfonamide 155 (S)-1′-(6-methyl-3-(1H-pyrazol-5-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 156 (S)-2-(3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(8- chlorochroman-7-yl)-5-methylpyrazin-2-yl)propan-2-ol 157 (S)-6-chloro-1′-(5-(7-chloro-2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 158 (S)-4-bromo-1′-(5-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 159 (S)-1-amino-1′-(6-cyano-5-(1H-indazol-7-yl)pyrazin-2-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′- piperidine]-6-carboxamide 160 (S)-1′-(5-(1H-indol-3-yl)-6-iodopyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 161 (R)-6-(5-(7′-amino-7′,8′-dihydro-5′H-spiro[piperidine-4,6′-quinolin]-1-yl)-3-vinylpyrazin-2- yl)isoindolin-1-one 162 (R)-1-(4-(5-(6-amino-6,7-dihydrospiro[cyclopenta[b]pyridine-5,4′-piperidin]-1′-yl)-3- ethylpyrazin-2-yl)-3,3-difluoroindolin-1-yl)ethan-1-one 163 (S)-1′-(5-(3-methyl-1H-indazol-6-yl)-6-phenylpyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 164 (S)-1′-(5-(1H-benzo[d][1,2,3]triazol-6-yl)-6-cyclopropylpyrazin-2-yl)-6-((tetrahydro-2H-pyran- 4-yl)oxy)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 165 (S)-1-amino-1′-(3-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 166 (S)-1′-(3-(1H-benzo[d]imidazol-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 167 (S)-1-(6-(1-amino-5-chloro-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one 168 (1-(6-((S)-1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)methanol 169 1-(6-((1S)-1-amino-6-(methylsulfinyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-5-fluoro-1,2,3,4-tetrahydroquinoline-6-carbonitrile 170 (S)-6-chloro-1′-(3-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5-methyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 171 (S)-5-(6-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4- b]pyrazin-3-yl)-N-(2-methoxyethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxamide 172 (S)-1-amino-5-fluoro-1′-(3-(6-(piperazin-1-yl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 173 (S)-2-(1-(6-(1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylic acid 174 (S)-1′-(6-(aminomethyl)-5-(2,3-dichloropyridin-4-yl)pyrazin-2-yl)-6-(1H-imidazol-1-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 175 (1S)-1-amino-1′-(5-(2,3-dichloropyridin-4-yl)-3-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-6- methylpyrazin-2-yl)-N,N-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carboxamide 176 (S)-1′-(8-(2-amino-3-chloropyridin-4-yl)-7-methylimidazo[1,2-c]pyrimidin-5-yl)-5-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 177 (S)-1′-(5-(1-methyl-1H-indol-2-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3,3-d2- 1-amine 178 (S)-1-(6-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one 179 (S)-1′-(3-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine 180 (3-((S)-1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((R)-1- methylisoindolin-2-yl)pyrazin-2-yl)methanol 181 (S)-1′-(3-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5,5-d2-7-amine 182 (S)-4-(difluoromethyl)-1′-(5-methyl-6-((R)-2-methyl-3,4-dihydro-1,5-naphthyridin-1(2H)- yl)pyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 183 (S)-1′-(8-(2-chloro-3-(isopropyl(methyl)amino)phenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)- 2,3,6,8-tetrahydrospiro[indeno[5,6-b][1,4]dioxine-7,4′-piperidin]-6-amine 184 (S)-1-(5-amino-1′-(8-((5-chloro-1-methylindolin-6-yl)thio)imidazo[1,5-a]pyridin-5-yl)-2,3,5,7- tetrahydro-1H-spiro[cyclopenta[b]pyrrolo[3,2-e]pyridine-6,4′-piperidin]-1-yl)ethan-1-one


340. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-339 and at least one pharmaceutically acceptable excipient.
 341. The pharmaceutical composition of claim 340, wherein, the compound in a weight ratio to the said excipient within the range from about 0.0001 to about
 10. 342. A combination pharmaceutical product comprising the compound or a pharmaceutically acceptable salt thereof of any of claims 1-339, together with one or more other therapeutically active agents.
 343. Use of the compound or a pharmaceutically acceptable salt thereof of any one of claim 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342 for the preparation of a medicament.
 344. The use of claim 343, wherein the medicament is used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.
 345. Use, in the manufacture of a medicament for use as an inhibitor of SHP2, of at least one compound or a pharmaceutically acceptable salt thereof any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim
 342. 346. Use of the compound or a pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342 for the preparation of a medicament in the treatment of diseases or conditions mediated by the activity of SHP2.
 347. The use of claim 346, wherein the diseases or conditions mediated by the activity of SHP2 is cancer.
 348. The use of claim 346, wherein the diseases or conditions mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.
 349. A method for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease, comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claims 340 or 341, or the combination pharmaceutical product of claim 342, wherein the disease is cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.
 350. A method for inhibiting the activity of SHP2 level, comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, or the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim
 342. 351. A method for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease, comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342, wherein the disease is mediated by the activity of SHP2.
 352. The method of claim 351, wherein the disease mediated by the activity of SHP2 is cancer.
 353. The method of claim 351, wherein the disease mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.
 354. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342 for use in preventing or treating a disease, lessening a disease symptom, delaying the progression or onset of a disease, wherein the disease is cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.
 355. The compound or the pharmaceutically acceptable slat thereof any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 339, for use in inhibiting the activity of SHP2.
 356. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 339 for use in preventing or treating a disease, lessening a disease symptom, delaying the progression or onset of a disease, wherein the disease is mediated by the activity of SHP2.
 357. The compound or the pharmaceutically acceptable salt thereof, the pharmaceutical composition, or the combination pharmaceutical product of claim 356, wherein the disease mediated by the activity of SHP2 is cancer.
 358. The compound or the pharmaceutically acceptable salt thereof, the pharmaceutical composition, or the combination pharmaceutical product of claim 356, wherein the disease mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma. 